ORCID Profile
0000-0002-7590-7390
Current Organisations
The University of Queensland Queensland Brain Institute
,
Washington University in St. Louis School of Medicine
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Neurosciences | Central Nervous System | Neurogenetics | Central Nervous System | Neurocognitive Patterns and Neural Networks | Genetics | Zoology | Neurogenetics | Decision Making | Epigenetics (incl. Genome Methylation and Epigenomics) | Gene Expression (incl. Microarray and other genome-wide approaches) | Animal Cell and Molecular Biology | Animal Neurobiology | Clinical Pharmacology And Therapeutics | Cognitive Science | Comparative Physiology |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Nervous System and Disorders | Nervous system and disorders | Expanding Knowledge in Psychology and Cognitive Sciences | Biological sciences | Inherited diseases (incl. gene therapy) | Expanding Knowledge in the Medical and Health Sciences | Mental health | Treatments (e.g. chemicals, antibiotics)
Related Links
Publications
YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
Publisher: Springer Science and Business Media LLC
Date: 02-09-2019
DOI: 10.1038/S41467-019-11884-5
Abstract: YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
Imaging, anatomical, and molecular analysis of callosal formation in the developing human fetal brain
Publisher: Wiley
Date: 12-01-2006
DOI: 10.1002/AR.A.20282
Abstract: A complex set of axonal guidance mechanisms are utilized by axons to locate and innervate their targets. In the developing mouse forebrain, we previously described several midline glial populations as well as various guidance molecules that regulate the formation of the corpus callosum. Since agenesis of the corpus callosum is associated with over 50 different human congenital syndromes, we wanted to investigate whether these same mechanisms also operate during human callosal development. Here we analyze midline glial and commissural development in human fetal brains ranging from 13 to 20 weeks of gestation using both diffusion tensor magnetic resonance imaging and immunohistochemistry. Through our combined radiological and histological studies, we demonstrate the morphological development of multiple forebrain commissures/decussations, including the corpus callosum, anterior commissure, hippoc al commissure, and the optic chiasm. Histological analyses demonstrated that all the midline glial populations previously described in mouse, as well as structures analogous to the subcallosal sling and cingulate pioneering axons, that mediate callosal axon guidance in mouse, are also present during human brain development. Finally, by Northern blot analysis, we have identified that molecules involved in mouse callosal development, including Slit, Robo, Netrin1, DCC, Nfia, Emx1, and GAP-43, are all expressed in human fetal brain. These data suggest that similar mechanisms and molecules required for midline commissure formation operate during both mouse and human brain development. Thus, the mouse is an excellent model system for studying normal and pathological commissural formation in human brain development.
The evolution, formation and connectivity of the anterior commissure
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.SEMCDB.2021.04.009
Abstract: The anterior commissure is the most ancient of the forebrain interhemispheric connections among all vertebrates. Indeed, it is the predominant pallial commissure in all non-eutherian vertebrates, universally subserving basic functions related to olfaction and survival. A key feature of the anterior commissure is its ability to convey connections from erse brain areas, such as most of the neocortex in non-eutherian mammals, thereby mediating the bilateral integration of erse functions. Shared developmental mechanisms between the anterior commissure and more evolutionarily recent commissures, such as the corpus callosum in eutherians, have led to the hypothesis that the former may have been a precursor for additional expansion of commissural circuits. However, differences between the formation of the anterior commissure and other telencephalic commissures suggest that independent developmental mechanisms underlie the emergence of these connections in extant species. Here, we review the developmental mechanisms and connectivity of the anterior commissure across evolutionarily distant species, and highlight its potential functional importance in humans, both in the course of normal neurodevelopment, and as a site of plastic axonal rerouting in the absence or damage of other connections.
Regulation of the early development of the nervous system by growth factors
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0163-7258(94)00044-1
Abstract: Development of the nervous system, although patterned by intrinsic genetic expression, appears to be dependent on growth factors for many of the differentiation steps that generate the wide variety of neurons and glia found in the both the central and peripheral nervous system. By using in vitro assays, including clonal analysis, the precise function of the various growth factors and the differentiation potential of the various neural populations has begun to be described. This review discusses some of the recent findings and examines how neuronal differentiation may result from the interaction of several growth factors.
Reducing the burden of neurological disease and mental illness
Publisher: AMPCo
Date: 05-2017
DOI: 10.5694/MJA17.00141
A role for cingulate pioneering axons in the development of the corpus callosum
Publisher: Wiley
Date: 2001
DOI: 10.1002/CNE.1170
Abstract: In many vertebrate and invertebrate systems, pioneering axons play a crucial role in establishing large axon tracts. Previous studies have addressed whether the first axons to cross the midline to from the corpus callosum arise from neurons in either the cingulate cortex (Koester and O'Leary [1994] J. Neurosci. 11:6608-6620) or the rostrolateral neocortex (Ozaki and Wahlsten [1998] J. Comp. Neurol. 400:197-206). However, these studies have not provided a consensus on which populations pioneer the corpus callosum. We have found that neurons within the cingulate cortex project axons that cross the midline and enter the contralateral hemisphere at E15.5. By using different carbocyanine dyes injected into either the cingulate cortex or the neocortex of the same brain, we found that cingulate axons crossed the midline before neocortical axons and projected into the contralateral cortex. Furthermore, the first neocortical axons to reach the midline crossed within the tract formed by these cingulate callosal axons, and appeared to fasciculate with them as they crossed the midline. These data indicate that axons from the cingulate cortex might pioneer a pathway for later arriving neocortical axons that form the corpus callosum. We also found that a small number of cingulate axons project to the septum as well as to the ipsilateral hippoc us via the fornix. In addition, we found that neurons in the cingulate cortex projected laterally to the rostrolateral neocortex at least 1 day before the neocortical axons reach the midline. Because the rostrolateral neocortex is the first neocortical region to develop, it sends the first neocortical axons to the midline to form the corpus callosum. We postulate that, together, both laterally and medially projecting cingulate axons may pioneer a path for the medially directed neocortical axons, thus helping to guide these axons toward and across the midline during the formation of the corpus callosum.
Absence of the transcription factorNfibdelays the formation of the basilar pontine and other mossy fiber nuclei
Publisher: Wiley
Date: 03-2009
DOI: 10.1002/CNE.21943
Abstract: Transcription factors of the Nuclear Factor I (Nfi) family are important for the development of specific neuronal and glial populations in the nervous system. One such population, the neurons of the basilar pontine nuclei, expresses high levels of Nfi proteins, and the pontine nuclei are greatly reduced in mice lacking a functional Nfib gene. Pontine neurons, along with other precerebellar neurons that populate the hindbrain, arise from precursors in the lower rhombic lip and migrate anteroventrally to reach their final location. Using immunohistochemistry, we find that NFI-B expression is specific for mossy fiber populations of the precerebellar system. Analysis of the Nfib(-/-) hindbrain indicates that the development of the basilar pontine nuclei is delayed, with pontine neurons migrating 1-2 days later than in control animals, and that significantly fewer pontine neurons are produced. While the mossy fiber nuclei of the caudal medulla do form, they also exhibit a developmental delay. Nfia and Nfix null mice exhibit no apparent pontine phenotype, implying specificity in the action of NFI family members. Collectively, these data demonstrate that Nfib plays an important role in the generation of precerebellar mossy fiber neurons, and may do so at least in part by regulating neurogenesis.
Non-uniform temporal scaling of developmental processes in the mammalian cortex
Publisher: Springer Science and Business Media LLC
Date: 23-09-2023
A Bayesian model predicts the response of axons to molecular gradients
Publisher: Proceedings of the National Academy of Sciences
Date: 23-06-2009
Abstract: Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.
Robos are required for the correct targeting of retinal ganglion cell axons in the visual pathway of the brain
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.MCN.2007.12.017
Abstract: Axonal projections from the retina to the brain are regulated by molecules including the Slit family of ligands [Thompson, H., Barker, D., Camand, O., Erskine, L., 2006a. Slits contribute to the guidance of retinal ganglion cell axons in the mammalian optic tract. Dev. Biol. 296, 476-484, Thompson, H., Camand, O., Barker, D., Erskine, L., 2006b. Slit proteins regulate distinct aspects of retinal ganglion cell axon guidance within dorsal and ventral retina. J. Neurosci. 26, 8082-8091]. However, the roles of Slit receptors in mammals, (termed Robos), have not been investigated in visual system development. Here we examined Robo1 and 2 mutant mice and found that Robos regulate the correct targeting of retinal ganglion cell (RGC) axons along the entire visual projection. We noted aberrant projections of RGC axons into the cerebral cortex, an area not normally targeted by RGC axons. The optic chiasm was expanded along the rostro-caudal axis (similar to Slit mutant mice, Plump, A.S., Erskine, L., Sabatier, C., Brose, K., Epstein, C.J., Goodman, C.S., Mason, C.A., Tessier-Lavigne, M., 2002. Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 33, 219-232), with ectopic crossing points, and some axons projecting caudally toward the corticospinal tract. Further, we found that axons exuberantly projected into the diencephalon. These defects were more pronounced in Robo2 than Robo1 knockout animals, implicating Robo2 as the predominant Robo receptor in visual system development.
Variants in nuclear factor I genes influence growth and development
Publisher: Wiley
Date: 15-11-2019
DOI: 10.1002/AJMG.C.31747
Abstract: The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in in iduals with intellectual disability and brain overgrowth, with in idual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.
Labeling neural cells using adenoviral gene transfer of membrane-targeted GFP
Publisher: Elsevier BV
Date: 02-1996
DOI: 10.1016/S0896-6273(00)80044-6
Abstract: We describe an experimental system to visualize the soma and processes of mammalian neurons and glia in living and fixed preparations by using a recombinant adenovirus vector to transfer the jellyfish green fluorescent protein (GFP) into postmitotic neural cells both in vitro and in vivo. We have introduced several modifications of GFP that enhance its fluorescence intensity in mammalian axons and dendrites. This method should be useful for studying the dynamic processes of cell migration and the development of neuronal connections, as well as for analyzing the function of exogenous genes introduced into cells using the adenovirus vector.
Transcriptional regulation of Nfix by NFIB drives astrocytic maturation within the developing spinal cord
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.YDBIO.2017.10.019
Abstract: During mouse spinal cord development, ventricular zone progenitor cells transition from producing neurons to producing glia at approximately embryonic day 11.5, a process known as the gliogenic switch. The transcription factors Nuclear Factor I (NFI) A and B initiate this developmental transition, but the contribution of a third NFI member, NFIX, remains unknown. Here, we reveal that ventricular zone progenitor cells within the spinal cord express NFIX after the onset of NFIA and NFIB expression, and after the gliogenic switch has occurred. Mice lacking NFIX exhibit normal neurogenesis within the spinal cord, and, while early astrocytic differentiation proceeds normally, aspects of terminal astrocytic differentiation are impaired. Finally, we report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. This hierarchical organisation of NFI protein expression and function during spinal cord gliogenesis reveals a previously unrecognised auto-regulatory mechanism within this gene family.
The anatomy, organisation and development of contralateral callosal projections of the mouse somatosensory cortex
Publisher: SAGE Publications
Date: 2017
Abstract: Alterations in the development of neuronal connectivity can result in dramatic outcomes for brain function. In the cerebral cortex, most sensorimotor and higher-order functions require coordination between precise regions of both hemispheres through the axons that form the corpus callosum. However, little is known about how callosal axons locate and innervate their contralateral targets. Here, we use a combination of in utero electroporation, retrograde tracing, sensory deprivation and high-resolution axonal quantification to investigate the development, organisation and activity dependence of callosal axons arising from the primary somatosensory cortex of mice. We show that distinct contralateral projections arise from different neuronal populations and form homotopic and heterotopic circuits. Callosal axons innervate the contralateral hemisphere following a dorsomedial to ventrolateral and region-specific order. Furthermore, we identify two periods of region- and layer-specific developmental exuberance that correspond to initial callosal axon innervation and subsequent arborisation. Early sensory deprivation affects only the latter of these events. Taken together, these results reveal the main developmental events of contralateral callosal targeting and may aid future understanding of the formation and pathologies of brain connectivity.
Expression of nuclear factor one A and ‐B in the olfactory bulb
Publisher: Wiley
Date: 02-06-2014
DOI: 10.1002/CNE.23574
Wnt5a induces Ryk-dependent and -independent effects on callosal axon and dendrite growth
Publisher: Informa UK Limited
Date: 28-01-2014
DOI: 10.3109/08977194.2013.875544
Abstract: The non-canonical Wnt receptor, Ryk, promotes chemorepulsive axon guidance in the developing mouse brain and spinal cord in response to Wnt5a. Ryk has also been identified as a major suppressor of axonal regrowth after spinal cord injury. Thus, a comprehensive understanding of how growing axons and dendrites respond to Wnt5a-mediated Ryk activation is required if we are to overcome this detrimental activity. Here we undertook a detailed analysis of the effect of Wnt5a/Ryk interactions on axonal and dendritic growth in dissociated embryonic mouse cortical neuron cultures, focusing on callosal neurons known to be responsive to Ryk-induced chemorepulsion. We show that Ryk inhibits axonal growth in response to Wnt5a. We also show that Wnt5a inhibits dendrite growth independently of Ryk. However, this inhibition is relieved when Ryk is present. Therefore, Wnt5a-mediated Ryk activation triggers ergent responses in callosal axons and dendrites in the in vitro context.
An MRI-based atlas and database of the developing mouse brain
Publisher: Elsevier BV
Date: 2011
Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2019
DOI: 10.1101/691303
Abstract: Astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation and therefore could be effectors of cellular differentiation in glioblastoma. We analysed expression of family members NFIA and NFIB using high-grade astrocytoma mRNA expression datasets, and with immunofluorescence co-staining. Their expression is reduced in glioblastomas and is associated with differentiated and mature astrocyte-like cells at a cellular level. Furthermore, induction of NFI expression is sufficient to promote cellular differentiation in patient-derived glioblastoma xenografts. Our findings indicate that NFI proteins may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal development. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
International Brain Initiative: An Innovative Framework for Coordinated Global Brain Research Efforts
Publisher: Elsevier BV
Date: 03-2020
Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations
Publisher: Wiley
Date: 14-02-2020
DOI: 10.1111/DMCN.14486
Abstract: Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 in iduals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.
Leukemia inhibitory factor prevents the death of axotomised sensory neurons in the dorsal root ganglia of the neonatal rat
Publisher: Wiley
Date: 02-1994
Abstract: Leukemia inhibitory factor (LIF) has several characteristics of a neurotrophic factor for sensory neurons. Here we have investigated whether LIF also supports the survival of axotomised sensory neurons in vivo. Newborn rat pups received a unilateral sciatic nerve transection and the injury site was treated with gelfoam soaked in phosphate buffered saline (PBS), nerve growth factor (NGF), or LIF. Neuronal nucleoli in the L5 dorsal root ganglia were counted, appropriate corrections applied, and the resultant neuronal loss expressed as a percentage of the contralateral intact side. In animals where LIF was administered neuronal loss was significantly reduced: 2 days after LIF treatment neuronal loss was 19.5% compared to 43% in PBS-treated animals 3 days after LIF treatment neuronal loss was 20.4% compared to 40.2% in PBS-treated animals however, 7 days after LIF treatment there was no significant reduction in the number of neurons lost. The degree of rescue of sensory neurons in vivo by LIF was found to be similar to NGF, which was not surprising as both factors supported the survival of a similar population of sensory neurons in vitro. Rescue was not observed when LIF-containing gelfoam was placed away from the axotomised nerve, suggesting that LIF's action may be associated with its retrograde transport or direct signalling at the site of nerve injury.
Lineage specification of neuronal precursors in the mouse spinal cord.
Publisher: Proceedings of the National Academy of Sciences
Date: 24-10-1995
Abstract: We have investigated the differentiation potential of precursor cells within the developing spinal cord of mice and have shown that spinal cord cells from embryonic day 10 specifically give rise to neurons when plated onto an astrocytic monolayer, Ast-1. These neurons had the morphology of motor neurons and 83% expressed the motor neuron markers choline acetyltransferase, peripherin, calcitonin gene-related peptide, and L-14. By comparison, 10% of the neurons arising on monolayers of other neural cell lines or 3T3 fibroblasts had motor neuron characteristics. Cells derived from dorsal, intermediate, and ventral regions of the spinal cord all behaved similarly and gave rise to motor neuron-like cells when plated onto Ast-1. By using cells that expressed the lacZ reporter gene, it was shown that 93% of cells present on the Ast-1 monolayers were motor neuron-like. Time-lapse analysis revealed that the precursors on the Ast-1 monolayers gave rise to neurons either directly or following a single cell ision. Together, these results indicate that precursors in the murine spinal cord can be induced to differentiate into the motor neuron phenotype by factors produced by Ast-1 cells, suggesting that a similar factor(s) produced by cells akin to Ast-1 may regulate motor neuron differentiation in vivo.
Multiple Slits regulate the development of midline glial populations and the corpus callosum
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.YDBIO.2012.02.004
Abstract: The Slit molecules are chemorepulsive ligands that regulate axon guidance at the midline of both vertebrates and invertebrates. In mammals, there are three Slit genes, but only Slit2 has been studied in any detail with regard to mammalian brain commissure formation. Here, we sought to understand the relative contributions that Slit proteins make to the formation of the largest brain commissure, the corpus callosum. Slit ligands bind Robo receptors, and previous studies have shown that Robo1(-/-) mice have defects in corpus callosum development. However, whether the Slit genes signal exclusively through Robo1 during callosal formation is unclear. To investigate this, we compared the development of the corpus callosum in both Slit2(-/-) and Robo1(-/-) mice using diffusion magnetic resonance imaging. This analysis demonstrated similarities in the phenotypes of these mice, but crucially also highlighted subtle differences, particularly with regard to the guidance of post-crossing axons. Analysis of single mutations in Slit family members revealed corpus callosum defects (but not complete agenesis) in 100% of Slit2(-/-) mice and 30% of Slit3(-/-) mice, whereas 100% of Slit1(-/-) Slit2(-/-) mice displayed complete agenesis of the corpus callosum. These results revealed a role for Slit1 in corpus callosum development, and demonstrated that Slit2 was necessary but not sufficient for midline crossing in vivo. However, co-culture experiments utilising Robo1(-/-) tissue versus Slit2 expressing cell blocks demonstrated that Slit2 was sufficient for the guidance activity mediated by Robo1 in pre-crossing neocortical axons. This suggested that Slit1 and Slit3 might also be involved in regulating other mechanisms that allow the corpus callosum to form, such as the establishment of midline glial populations. Investigation of this revealed defects in the development and dorso-ventral positioning of the indusium griseum glia in multiple Slit mutants. These findings indicate that Slits regulate callosal development via both classical chemorepulsive mechanisms, and via a novel role in mediating the correct positioning of midline glial populations. Finally, our data also indicate that some of the roles of Slit proteins at the midline may be independent of Robo signalling, suggestive of additional receptors regulating Slit signalling during development.
The convergent roles of the nuclear factor I transcription factors in development and cancer
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.CANLET.2017.09.015
Abstract: The nuclear factor I (NFI) transcription factors play important roles during normal development and have been associated with developmental abnormalities in humans. All four family members, NFIA, NFIB, NFIC and NFIX, have a homologous DNA binding domain and function by regulating cell proliferation and differentiation via the transcriptional control of their target genes. More recently, NFI genes have also been implicated in cancer based on genomic analyses and studies of animal models in a variety of tumours across multiple organ systems. However, the association between their functions in development and in cancer is not well described. In this review, we summarise the evidence suggesting a converging role for the NFI genes in development and cancer. Our review includes all cancer types in which the NFI genes are implicated, focusing predominantly on studies demonstrating their oncogenic or tumour-suppressive potential. We conclude by presenting the challenges impeding our understanding of NFI function in cancer biology, and demonstrate how a developmental perspective may contribute towards overcoming such hurdles.
Surrounded by Slit - How forebrain commissural axons can be led astray
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S0896-6273(02)00566-4
Abstract: In Drosophila, Slit acts as a barrier preventing roundabout expressing axons from entering the midline and sorting contralaterally from ipsilaterally projecting axons. Hutson and Chien, Plump et al., and Bagri et al. (all in this issue of Neuron) use Slit knockout mice and zebrafish astray/Robo2 mutants to show that in vertebrates, Robo/Slit function to channel axons into specific pathways and determine where decussation points occur. Ipsilaterally and contralaterally projected axons are equally affected.
Development of body, head and brain features in the Australian fat-tailed dunnart (Sminthopsis crassicaudata; Marsupialia: Dasyuridae); A postnatal model of forebrain formation
Publisher: Public Library of Science (PLoS)
Date: 07-09-2017
PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2018
DOI: 10.1101/317974
Abstract: De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.
Contralateral targeting of the corpus callosum in normal and pathological brain function
Publisher: Elsevier BV
Date: 05-2015
A brief history of the Australasian Neuroscience Society
Publisher: Informa UK Limited
Date: 09-09-2021
Teaching NeuroImages: Imaging features of DCC-mediated mirror movements and isolated agenesis of the corpus callosum
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-08-2018
DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation
Publisher: eLife Sciences Publications, Ltd
Date: 04-05-2021
DOI: 10.7554/ELIFE.61618
Abstract: Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base-pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.
DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation
Publisher: Cold Spring Harbor Laboratory
Date: 30-07-2020
DOI: 10.1101/2020.07.29.227827
Abstract: Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR acallosal strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.
Transcriptional regulation of intermediate progenitor cell generation during hippocampal development
Publisher: The Company of Biologists
Date: 15-12-2016
DOI: 10.1242/DEV.140681
Abstract: During forebrain development, radial glia generate neurons through the production of intermediate progenitor cells (IPCs). The production of IPCs is a central tenet underlying the generation of the appropriate number of cortical neurons, but the transcriptional logic underpinning this process remains poorly defined. Here, we examined IPC production using mice lacking the transcription factor nuclear factor I/X (Nfix). We show that Nfix deficiency delays IPC production and prolongs the neurogenic window, resulting in an increased number of neurons in the postnatal forebrain. Loss of additional Nfi alleles (Nfib) resulted in a severe delay in IPC generation while, conversely, overexpression of NFIX led to precocious IPC generation. Mechanistically, analyses of microarray and ChIP-seq datasets, coupled with the investigation of spindle orientation during radial glial cell ision, revealed that NFIX promotes the generation of IPCs via the transcriptional upregulation of inscuteable (Insc). These data thereby provide novel insights into the mechanisms controlling the timely transition of radial glia into IPCs during forebrain development.
Regulation of the Early Development of the Nervous System by Growth Factors
Publisher: Springer US
Date: 1992
A comprehensive evaluation of the longitudinal association between alcohol consumption and a measure of inflammation: Multiverse and vibration of effects analyses
Publisher: Elsevier BV
Date: 06-2023
Understanding the Mechanisms of Callosal Development Through the Use of Transgenic Mouse Models
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.SPEN.2009.07.003
Abstract: The cerebral cortex is the area of the brain where higher-order cognitive processing occurs. The 2 hemispheres of the cerebral cortex communicate through one of the largest fiber tracts in the brain, the corpus callosum. Malformation of the corpus callosum in human beings occurs in 1 in 4000 live births, and those afflicted experience an extensive range of neurologic disorders, from relatively mild to severe cognitive deficits. Understanding the molecular and cellular processes involved in these disorders would therefore assist in the development of prognostic tools and therapies. During the past 3 decades, mouse models have been used extensively to determine which molecules play a role in the complex regulation of corpus callosum development. This review provides an update on these studies, as well as highlights the value of using mouse models with the goal of developing therapies for human acallosal syndromes.
Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta‐analysis consisting 2.8 million adults with 57 294 cases of dementia
Publisher: Wiley
Date: 03-01-2020
DOI: 10.1111/OBR.12989
The regulation of neural precursor cells within the mammalian brain
Publisher: Elsevier BV
Date: 02-1995
Divergent evolution of developmental timing in the neocortex revealed by marsupial and eutherian transcriptomes.
Publisher: The Company of Biologists
Date: 02-2022
DOI: 10.1242/DEV.200212
Abstract: Only mammals evolved a neocortex, which integrates sensory-motor and cognitive functions. Significant ersifications in the cellular composition and connectivity of the neocortex occurred between the two main therian groups: marsupials and eutherians. However, the developmental mechanisms underlying these ersifications are largely unknown. Here, we compared the neocortical transcriptomes of Sminthopsis crassicaudata, a mouse-sized marsupial, with those of eutherian mice at two developmentally equivalent time points corresponding to deeper and upper layer neuron generation. Enrichment analyses revealed more mature gene networks in marsupials at the early stage, which reverted at the later stage, suggesting a more precocious but protracted neuronal maturation program relative to birth timing of cortical layers. We ranked genes expressed in different species and identified important differences in gene expression rankings between species. For ex le, genes known to be enriched in upper-layer cortical projection neuron subtypes, such as Cux1, Lhx2 and Satb2, likely relate to corpus callosum emergence in eutherians. These results show molecular heterochronies of neocortical development in Theria, and highlight changes in gene expression and cell type composition that may underlie neocortical evolution and ersification. This article has an associated 'The people behind the papers' interview.
Erratum: A new chemotaxis assay shows the extreme sensitivity of axons to molecular gradients
Publisher: Springer Science and Business Media LLC
Date: 07-2004
DOI: 10.1038/NN0704-785
EMX2 transcriptionally regulates Nfib expression in neural progenitor cells during early cortical development
Publisher: Cold Spring Harbor Laboratory
Date: 26-12-2021
DOI: 10.1101/2021.12.26.474186
Abstract: The nuclear factor one (NFI) transcription factors play key roles in regulating the onset of both neuronal and glial differentiation during cortical development. Reduced NFI expression results in delayed differentiation, which is associated with neurodevelopmental disorders in humans that include intellectual disability, agenesis of the corpus callosum and macrocephaly. Despite their importance, our understanding of how in idual NFI family members are regulated during cortical development remains limited. Here, we demonstrate that in mice, the homeobox transcription factor EMX2 regulates Nfib expression in radial glial cells during cortical development. Using a combination of bioinformatics, molecular and histological approaches, we demonstrate that EMX2 is able to bind to the Nfib promoter to up-regulate Nfib expression. Unexpectedly, in vivo over-expression of EMX2 in wildtype animals does not further up-regulate NFIB but instead leads to its down-regulation. Therefore, our findings suggest that EMX2 is capable of both activating and repressing Nfib , in a context-dependent manner. This bi-directional control over Nfib expression enables fine-tuning of the total level of NFI proteins expressed and could be important for cell-type specific NFI functions.
Evolution and development of interhemispheric connections in the vertebrate forebrain
Publisher: Frontiers Media SA
Date: 14-07-2014
Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41467-017-02719-2
Abstract: Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the in idual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of in idual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.
Neuropilin-1 Conveys Semaphorin and VEGF Signaling during Neural and Cardiovascular Development
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S1534-5807(03)00169-2
Abstract: Neuropilin-1 (Npn-1) is a receptor that binds multiple ligands from structurally distinct families, including secreted semaphorins (Sema) and vascular endothelial growth factors (VEGF). We generated npn-1 knockin mice, which express an altered ligand binding site variant of Npn-1, and npn-1 conditional null mice to establish the cell-type- and ligand specificity of Npn-1 function in the developing cardiovascular and nervous systems. Our results show that VEGF-Npn-1 signaling in endothelial cells is required for angiogenesis. In striking contrast, Sema-Npn-1 signaling is not essential for general vascular development but is required for axonal pathfinding by several populations of neurons in the CNS and PNS. Remarkably, both Sema-Npn-1 signaling and VEGF-Npn-1 signaling are critical for heart development. Therefore, Npn-1 is a multifunctional receptor that mediates the activities of structurally distinct ligands during development of the heart, vasculature, and nervous system.
Author response: DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation
Publisher: eLife Sciences Publications, Ltd
Date: 12-03-2021
DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.CELREP.2018.01.004
Abstract: Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis.
Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance
Publisher: Springer Science and Business Media LLC
Date: 27-02-2017
DOI: 10.1038/NG.3794
Development of the perforating pathway: An ipsilaterally projecting pathway between the medial septum/diagonal band of broca and the cingulate cortex that intersects the corpus callosum
Publisher: Wiley
Date: 2001
DOI: 10.1002/CNE.1077
Abstract: The perforating pathway (PFP) intersects the corpus callosum perpendicularly at the midline in the dorsoventral axis. Therefore axons in either the PFP or the corpus callosum make different axonal guidance decisions in the same anatomical region of the developing cortical midline. The mechanisms underlying these axonal choices are not known. To begin to identify these guidance mechanisms, we characterized the development of these two pathways in detail. The development of the corpus callosum and its pioneering projections has been described elsewhere (Shu and Richards [2001] J. Neurosci. 21:2749--2758 Rash and Richards [2001] J. Comp. Neurol. 434:147--157). Here we examine the development, origins, and projections of axons that make up the PFP. The majority of axons within the PFP originate from neurons in the medial septum and diagonal band of Broca complex. These neurons project in a topographic manner to the cingulate cortex. In contrast to previous reports, we find that a much smaller projection originating from the cingulate cortex also contributes to this pathway. The pioneering projections of the PFP and the corpus callosum arrive at the corticoseptal boundary at around the same developmental stage. These findings show that ipsilaterally projecting PFP axons and contralaterally projecting callosal axons make distinct guidance decisions at the same developmental stage when they reach the corticoseptal boundary.
Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2022
DOI: 10.1161/CIRCULATIONAHA.122.060700
Abstract: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Observational analyses were conducted using in idual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values or mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR mL·min –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
Why Schizophrenia Epidemiology Needs Neurobiology - and Vice Versa
Publisher: Oxford University Press (OUP)
Date: 30-03-2009
World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions
Publisher: Elsevier BV
Date: 10-2019
Subdomain-Mediated Axon-Axon Signaling and Chemoattraction Cooperate to Regulate Afferent Innervation of the Lateral Habenula
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.NEURON.2014.05.036
Abstract: A dominant feature of neural circuitry is the organization of neuronal projections and synapses into specific brain nuclei or laminae. Lamina-specific connectivity is controlled by the selective expression of extracellular guidance and adhesion molecules in the target field. However, how (sub)nucleus-specific connections are established and whether axon-derived cues contribute to subdomain targeting are largely unknown. Here, we demonstrate that the lateral subnucleus of the habenula (lHb) determines its own afferent innervation by sending out efferent projections that express the cell adhesion molecule LAMP to reciprocally collect and guide dopaminergic afferents to the lHb-a phenomenon we term subdomain-mediated axon-axon signaling. This process of reciprocal axon-axon interactions cooperates with lHb-specific chemoattraction mediated by Netrin-1, which controls axon target entry, to ensure specific innervation of the lHb. We propose that cooperation between pretarget reciprocal axon-axon signaling and subdomain-restricted instructive cues provides a highly precise and general mechanism to establish subdomain-specific neural circuitry.
Cyclic nucleotide-dependent switching of mammalian axon guidance depends on gradient steepness
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.MCN.2011.02.012
Abstract: Correct wiring of the nervous system during development requires axons to respond appropriately to gradients of attractive and repulsive guidance cues. However, the steepness and concentration of these gradients vary in vivo, for instance, with distance from the target. Understanding how these changing conditions affect the navigation strategies used by developing axons is important for understanding how they are guided over long distances. Previous work has shown that cyclic nucleotide levels determine whether axons are attracted or repelled by steep gradients of the same guidance cue, but it is unknown whether this is also true for shallow gradients. We therefore investigated the guidance responses of rat superior cervical ganglion (SCG) axons in both steep and shallow gradients of nerve growth factor (NGF). In steep gradients we found that cyclic nucleotide-dependent switching occurred, consistent with previous reports. Surprisingly however, we found that in shallow NGF gradients, cyclic nucleotide-dependent switching did not occur. These results suggest that there may be substantial differences in the way axons respond to gradient-based guidance cues depending on where they are within the gradient.
Axon position within the corpus callosum determines contralateral cortical projection
Publisher: Proceedings of the National Academy of Sciences
Date: 28-06-2013
Abstract: Two hemispheres of the neocortex are connected via a large axon bundle, the corpus callosum (CC). Axons from one side of the cortex project primarily to the equivalent cortical area on the contralateral side. How this homotopic axon projection is achieved during development remains unclear. Quantitative analysis of the cortical axons' positions within CC and their projection pattern after crossing the midline showed that axon position within CC is critical for homotopic projection. Further genetic perturbations of semaphorin/neuropilin-1 signaling disrupted the axon order in CC, resulting in an ectopic contralateral axon projection that could not be corrected by developmental refinement.
Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus
Publisher: Proceedings of the National Academy of Sciences
Date: 20-06-2011
Abstract: The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippoc us. Disrupting Lhx2 function in the embryonic hippoc us by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch-regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a “brake” on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippoc us, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippoc us and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon.
Mechanisms of Axon Guidance in the Developing Nervous System
Publisher: Elsevier
Date: 2005
MicroRNA-153 Regulates the Acquisition of Gliogenic Competence by Neural Stem Cells
Publisher: Elsevier BV
Date: 09-2015
A Neuroethics Framework for the Australian Brain Initiative
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEURON.2019.01.004
Abstract: Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.
Netrin-DCC Signaling Regulates Corpus Callosum Formation Through Attraction of Pioneering Axons and by Modulating Slit2-Mediated Repulsion
Publisher: Oxford University Press (OUP)
Date: 09-01-2013
Abstract: The left and right sides of the nervous system communicate via commissural axons that cross the midline during development using evolutionarily conserved molecules. These guidance cues have been particularly well studied in the mammalian spinal cord, but it remains unclear whether these guidance mechanisms for commissural axons are similar in the developing forebrain, in particular for the corpus callosum, the largest and most important commissure for cortical function. Here, we show that Netrin1 initially attracts callosal pioneering axons derived from the cingulate cortex, but surprisingly is not attractive for the neocortical callosal axons that make up the bulk of the projection. Instead, we show that Netrin-deleted in colorectal cancer signaling acts in a fundamentally different manner, to prevent the Slit2-mediated repulsion of precrossing axons thereby allowing them to approach and cross the midline. These results provide the first evidence for how callosal axons integrate multiple guidance cues to navigate the midline.
Axonal guidance: Making connections
Publisher: Springer New York
Date: 2016
Reply:ARID1Bmutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability
Publisher: Oxford University Press (OUP)
Date: 29-07-2016
DOI: 10.1093/BRAIN/AWW171
Erratum: A Neuroethics Framework for the Australian Brain Initiative (Neuron (2019) 101(3) (365–369), (S0896627319300054), (10.1016/j.neuron.2019.01.004))
Publisher: Elsevier BV
Date: 2020
Understanding the Uptake of Nanomedicines at Different Stages of Brain Cancer Using a Modular Nanocarrier Platform and Precision Bispecific Antibodies
Publisher: American Chemical Society (ACS)
Date: 28-04-2020
Heterozygosity for Nuclear Factor One X Affects Hippocampal-Dependent Behaviour in Mice
Publisher: Public Library of Science (PLoS)
Date: 11-06-2013
Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development
Publisher: Elsevier BV
Date: 05-2020
The International Brain Initiative: enabling collaborative science
Publisher: Elsevier BV
Date: 12-2021
Unc5C and DCC act downstream of Ctip2 and Satb2 and contribute to corpus callosum formation
Publisher: Springer Science and Business Media LLC
Date: 17-04-2014
DOI: 10.1038/NCOMMS4708
A diffusion MRI-based spatiotemporal continuum of the embryonic mouse brain for probing gene–neuroanatomy connections
Publisher: Proceedings of the National Academy of Sciences
Date: 14-02-2022
Abstract: We established an ultra high-resolution diffusion MRI atlas of the embryonic mouse brains from E10.5 to E15.5, which characterizes the continuous changes of brain morphology and microstructures at mesoscopic scale. By integrating gene-expression data into the spatiotemporal continuum, we can navigate the evolving landscape of gene expression and neuroanatomy across both spatial and temporal dimensions to visualize their interactions in normal and abnormal embryonic brain development. We also identified regional clusters with distinct developmental trajectories and identified gene-expression profiles that matched to these regional domains. The diffusion MRI–based continuum of the embryonic brain and the computational techniques presented in this study offer a valuable tool for systematic study of the genetic control of brain development.
Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis
Publisher: Cold Spring Harbor Laboratory
Date: 02-05-2018
DOI: 10.1101/312629
Abstract: Cognitive reasoning is thought to require functional interactions between whole-brain networks. Such networks rely on both cerebral hemispheres, with the corpus callosum providing cross-hemispheric communication. Here we used high-field functional magnetic resonance imaging (7T fMRI), a well validated cognitive task, and brain network analyses to investigate the functional networks underlying cognitive reasoning in in iduals with corpus callosum dysgenesis (CCD), an anatomical abnormality that affects the corpus callosum. Participants with CCD were asked to solve cognitive reasoning problems while their brain activity was measured using fMRI. The complexity of these problems was parametrically varied by changing the complexity of relations that needed to be established between shapes within each problem matrix. Behaviorally, participants showed a typical reduction in task performance as problem complexity increased. Task-evoked neural activity was observed in brain regions known to constitute two key cognitive control systems: the fronto-parietal and cingulo-opercular networks. Under low complexity demands, network topology and the patterns of local neural activity in the CCD group closely resembled those observed in neurotypical controls. By contrast, when asked to solve more complex problems, participants with CCD showed a reduction in neural activity and connectivity within the fronto-parietal network. These complexity-induced, as opposed to resting-state, differences in functional network activity help resolve the apparent paradox between preserved network architecture found at rest in CCD in iduals, and the heterogeneous deficits they display in response to cognitive task demands [preprint: 0.1101/312629 ].
A new chemotaxis assay shows the extreme sensitivity of axons to molecular gradients
Publisher: Springer Science and Business Media LLC
Date: 25-05-2004
DOI: 10.1038/NN1259
Australian Brain Alliance
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.NEURON.2016.10.038
Abstract: A proposal for an Australian Brain Initiative (ABI) is under development by members of the Australian Brain Alliance. Here we discuss the goals of the ABI, its areas of research focus, its context in the Australian research setting, and its necessity for ensuring continued success for Australian brain research.
Investigating early formation of the cerebral cortex by in utero electroporation: Methods and protocols
Publisher: Springer New York
Date: 2016
DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
Publisher: eLife Sciences Publications, Ltd
Date: 06-04-2018
DOI: 10.7554/ELIFE.61769
Abstract: The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippoc al commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome
Publisher: Hindawi Limited
Date: 11-11-2018
DOI: 10.1002/HUMU.23361
Leukaemia inhibitory factor rescues motoneurones from axotomy-induced cell death
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1994
DOI: 10.1097/00001756-199404000-00034
Abstract: The death of spinal motoneurones after axotomy provides a useful model for studying novel factors which prevent motoneurone loss in vivo. Peripheral nerves of newborn rats were unilaterally transected and treated with either a vehicle solution or leukaemia inhibitory factor (LIF). Compared with the vehicle controls, treatment with a gelfoam containing LIF significantly reduced motoneurone loss: from 38% to 22% after 3 days and from 55% to 38% after 7 days. The loss of motoneurones was further reduced by placing the LIF-containing gelfoam inside a silicone chamber: from 39% to 15% after 7 days, which represented a 62% rescue. Thus, LIF is a potential therapeutic agent for preventing the loss of injured or diseased motoneurones.
Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes
Publisher: Oxford University Press (OUP)
Date: 28-01-2014
DOI: 10.1093/BRAIN/AWT358
Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.BIOMATERIALS.2022.121416
Abstract: Personalised nanomedicine is an advancing field which has developed significant improvements for targeting therapeutics to aggressive cancer and with fewer side effects. The treatment of gliomas such as glioblastoma (or other brain tumours), with nanomedicine is complicated by a commonly poor accumulation of drugs in tumour tissue owing to the partially intact blood-brain barrier (BBB). Nonetheless, the BBB becomes compromised following surgical intervention, and gradually with disease progression. Increased vasculature permeability generated by a tumour, combined with decreased BBB integrity, offers a mechanism to enhance therapeutic outcomes. We monitored a spontaneous glioma tumour model in immunocompetent mice with ongoing T2-weighted and contrast-enhanced T1-weighted magnetic resonance imaging gradient echo and spin echo sequences to predict an optimal "leakiness" stage for nanomedicine injections. To ascertain the effectiveness of targeted nanomedicines in treating brain tumours, subsequent systemic administration of targeted hyperbranched polymers was then utislised, to deliver the therapeutic payload when both the tumour and brain vascularity had become sufficiently susceptible to allow drug accumulation. Treatment with either doxorubicin-loaded hyperbranched polymer, or the same nanomedicine targeted to an ephrin receptor (EphA2) using a bispecific antibody, resulted in uptake of chemotherapeutic doxorubicin in the tumour and in reduced tumour growth. Compared to vehicle and doxorubicin only, nanoparticle delivered doxorubicin resulted in increased tumour apoptosis, while averting cardiotoxicity. This suggests that polyethylene based (PEGylated)-nanoparticle delivered doxorubicin could provide a more efficient treatment in tumours with a disrupted BBB, and that treatment should commence immediately following detection of gadolinium permeability, with early detection and ongoing 'leakiness' monitoring in susceptible patients being a key factor.
Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis
Publisher: Elsevier BV
Date: 2019
NFIA and NFIB function as tumour suppressors in high-grade glioma in mice
Publisher: Oxford University Press (OUP)
Date: 21-12-2021
Abstract: Nuclear factor one (NFI) transcription factors are implicated in both brain development and cancer in mice and humans and play an essential role in glial differentiation. NFI expression is reduced in human astrocytoma s les, particularly those of higher grade, whereas over-expression of NFI protein can induce the differentiation of glioblastoma cells within human tumour xenografts and in glioblastoma cell lines in vitro. These data indicate that NFI proteins may act as tumour suppressors in glioma. To test this hypothesis, we generated complex mouse genetic crosses involving six alleles to target gene deletion of known tumour suppressor genes that induce endogenous high-grade glioma in mice, and overlaid this with loss of function Nfi mutant alleles, Nfia and Nfib, a reporter transgene and an inducible Cre allele. Deletion of Nfi resulted in reduced survival time of the mice, increased tumour load and a more aggressive tumour phenotype than observed in glioma mice with normal expression of NFI. Together, these data indicate that NFI genes represent a credible target for both diagnostic analyses and therapeutic strategies to combat high-grade glioma.
Correction: Transcriptional regulation of intermediate progenitor cell generation during hippocampal development (doi: 10.1242/dev.140681)
Publisher: The Company of Biologists
Date: 15-07-2018
DOI: 10.1242/DEV.169631
X-linked microtubule-associated protein, Mid1, regulates axon development
Publisher: Proceedings of the National Academy of Sciences
Date: 05-11-2013
Abstract: The gene responsible for the X-linked form of Opitz syndrome (OS), Midline-1 ( MID1 ), encodes an E3 ubiquitin ligase and was reported to guide the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). But whether and how it is involved in neural development is unclear. We demonstrate here that Mid1-dependent PP2Ac turnover is involved in axon development. Knocking down or knocking out Mid1 not only promotes axon growth and branching in vitro, but also accelerates axon elongation and disrupts the pattern of callosal projection in mouse cortex. These defects can be reversed by down-regulating the accumulated PP2Ac in Mid1-depleted cells. Dysfunction of this Mid1–PP2Ac pathway may underlie neural symptoms of OS patients.
Combined allelic dosage of Nfia and Nfib regulates cortical development
Publisher: SAGE Publications
Date: 2017
Abstract: Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate similar biological processes, as their expression patterns, regulation of target genes and in idual knockout phenotypes overlap. We hypothesised that the combined allelic loss of Nfia and Nfib would culminate in more severe defects in the cerebral cortex than loss of a single member. We combined immunofluorescence, co-immunoprecipitation, gene expression analysis and immunohistochemistry on knockout mouse models to investigate whether nuclear factor I A and nuclear factor I B function similarly and whether increasing allelic loss of Nfia and Nfib caused a more severe phenotype. We determined that the biological functions of nuclear factor I A and nuclear factor I B overlap during early cortical development. These proteins are co-expressed and can form heterodimers in vivo. Differentially regulated genes that are shared between Nfia and Nfib knockout mice are highly enriched for nuclear factor I binding sites in their promoters and are associated with neurodevelopment. We found that compound heterozygous deletion of both genes resulted in a cortical phenotype similar to that of single homozygous Nfia or Nfib knockout embryos. This was characterised by retention of the interhemispheric fissure, dysgenesis of the corpus callosum and a malformed dentate gyrus. Double homozygous knockout of Nfia and Nfib resulted in a more severe phenotype, with increased ventricular enlargement and decreased numbers of differentiated glia and neurons. In the developing cerebral cortex, nuclear factor I A and nuclear factor I B share similar biological functions and function additively, as the combined allelic loss of these genes directly correlates with the severity of the developmental brain phenotype.
Astroglial-mediated remodeling of the interhemispheric midline during telencephalic development is exclusive to eutherian mammals
Publisher: Springer Science and Business Media LLC
Date: 30-05-2017
Altered structural connectome in adolescent socially isolated mice
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.NEUROIMAGE.2016.06.037
Abstract: Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the experience by social isolation impairs white matter microstructures in the prefrontal cortex. However, the effect of social isolation may involve highly distributed brain networks, and therefore cannot be fully explained by a change of a single region. Here, we compared the connectomes of adolescent socially-isolated mice and normal-housed controls via diffusion magnetic resonance imaging. The isolated mice displayed an abnormal connectome, characterized by an increase in degree and reductions in measures such as modularity, small-worldness, and betweenness. The increase in degree was most evident in the dorsolateral orbitofrontal cortex, entorhinal cortex, and perirhinal cortex. In a connection-wise comparison, we revealed that most of the abnormal edges were inter-modular and inter-hemispheric connections of the dorsolateral orbitofrontal cortex. Further tractography-based analyses and histological examinations revealed microstructural changes in the forceps minor and lateral-cortical tracts that were associated with the dorsolateral orbitofrontal cortex. These changes of connectomes were correlated with fear memory deficits and hyper-locomotion activities induced by social isolation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may primarily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome.
Cloning and Cortical Expression of Rat Emx2 and Adenovirus-mediated Overexpression to Assess its Regulation of Area-specific Targeting of Thalamocortical Axons
Publisher: Oxford University Press (OUP)
Date: 06-2003
Abstract: A goal of this study was to use recombinant adenovirus (AdV) to ectopically express Emx2 in the embryonic neocortex as a gain-of-function approach to study its role in the area-specific targeting of thalamocortical axons (TCAs), using the rat as a model. First, we cloned the cDNA for the full-length coding region of rat Emx2, a homologue of Drosophila empty spiracles. We also used this sequence to define the full-length coding region of mouse Emx2 from genomic DNA. Our analysis of Emx2 expression shows that in rat, as reported in mouse, Emx2 is expressed in high caudal to low rostral, and high medial to low lateral, gradients across the cortex throughout cortical neurogenesis, and expression is primarily restricted to progenitors in the neuroepithelium. We also carried out an analysis of the distribution of cells infected with a replication defective recombinant type 5 adenovirus (AdV) containing a CAG/LacZ expression construct, following an injection into the lateral ventricle of the cerebral hemisphere at different stages of embryonic cortical neurogenesis. AdV-infected cells are broadly distributed tangentially, but their laminar distribution is differentially restricted and reflects the temporal sequence of generation of cortical neurons. This finding indicates that the AdV predominantly infects progenitors in the ventricular zone, which leads to a preferential labeling of their immediate progeny, and infects cells that have recently become postmitotic and have yet to move far from the ventricular surface. We then show that AdV-mediated ectopic Emx2 expression results in aberrant intracortical pathfinding and areal targeting of TCAs from the dorsal lateral geniculate nucleus. These findings indicate that EMX2 imparts positional information normally associated with caudal cortical areas, such as the primary visual area, that influences the area-specific targeting of TCAs. These results are consistent with a role for EMX2 in areal specification of the neocortex as suggested by recent analyses of Emx2 null mutants.
A pan-mammalian map of interhemispheric brain connections predates the evolution of the corpus callosum
Publisher: Proceedings of the National Academy of Sciences
Date: 04-09-2018
Abstract: The neocortex is a hallmark of mammalian evolution, and connections between both hemispheres integrate bilateral functions. In eutherians (e.g., rodents and humans), interhemispheric circuits course via the corpus callosum and share a similar connectome throughout species. Noneutherian mammals (i.e., monotremes and marsupials), however, did not evolve a corpus callosum therefore, whether the eutherian connectome arose as consequence of callosal evolution or instead reflects ancient connectivity principles remains unknown. We studied monotreme and marsupial interhemispheric neocortical connectomes and compared these with eutherian datasets. This revealed interhemispheric connectivity features shared across mammals, with or without a corpus callosum, suggesting that an ancient connectome originated at least 80 million years before callosal evolution.
Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
DOI: 10.1007/S11060-019-03352-3
Abstract: Malignant astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation to alter the behaviour of high-grade astrocytomas may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation. Here, we investigate whether family members NFIA and NFIB act as effectors of cellular differentiation in glioblastoma. We analysed expression of NFIA and NFIB in mRNA expression data of high-grade astrocytoma and with immunofluorescence co-staining. Furthermore, we induced NFI expression in patient-derived subcutaneous glioblastoma xenografts via in vivo electroporation. The expression of NFIA and NFIB is reduced in glioblastoma as compared to lower grade astrocytomas. At a cellular level, their expression is associated with differentiated and mature astrocyte-like tumour cells. In vivo analyses consistently demonstrate that expression of either NFIA or NFIB is sufficient to promote tumour cell differentiation in glioblastoma xenografts. Our findings indicate that both NFIA and NFIB may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal astrocyte differentiation. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
Increased persuadability and credulity in people with corpus callosum dysgenesis
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2021
DOI: 10.1101/2021.12.28.21268413
Abstract: Corpus callosum dysgenesis is one of the most common congenital neurological malformations. Despite being a clear and identifiable structural alteration of the brain’s white matter connectivity, the impact of corpus callosum dysgenesis on cognition and behaviour has remained unclear. Here we build upon past clinical observations in the literature to define the clinical phenotype of corpus callosum dysgenesis better using unadjusted and adjusted group differences compared with a neurotypical s le on a range of social and cognitive measures that have been previously reported to be impacted by a corpus callosum dysgenesis diagnosis. Those with a diagnosis of corpus callosum dysgenesis ( n = 22) demonstrated significantly higher persuadability, credulity, and insensitivity to social trickery than neurotypical ( n = 86) participants, after controlling for age, sex, education, autistic-like traits, social intelligence, and general cognition. To explore this further, machine learning, utilising a set neurotypical s le for training the normative covariance structure of our psychometric variables, was used to test whether these dimensions possessed the capability to discriminate between a test-set of neurotypical and corpus callosum dysgenesis participants. We found that participants with a diagnosis of corpus callosum dysgenesis were best classed within dimension space along the same axis as persuadability, credulity, and insensitivity to social trickery after controlling for age and sex, with Leave-One-Out-Cross-Validation across 250 training-set permutations providing a mean accuracy of 71.7%. These results have wide- reaching implications for a) the characterisation of corpus callosum dysgenesis, and b) the role of the corpus callosum in social inference.
Neuropilin 1-Sema Signaling Regulates Crossing of Cingulate Pioneering Axons during Development of the Corpus Callosum
Publisher: Oxford University Press (OUP)
Date: 08-04-2009
NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly
Publisher: Elsevier BV
Date: 11-2018
Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder
Publisher: Springer Science and Business Media LLC
Date: 03-04-2015
The transcription factor Nfixis essential for normal brain development
Publisher: Springer Science and Business Media LLC
Date: 13-05-2008
Abstract: The Nuclear Factor I (NFI) multi-gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia -deficient mice exhibit agenesis of the corpus callosum and other forebrain defects Nfib -deficient mice have defects in lung maturation and show callosal agenesis and forebrain defects resembling those seen in Nfia -deficient animals, while Nfic -deficient mice have defects in tooth root formation. Recently the Nfix gene has been disrupted and these studies indicated that there were largely uncharacterized defects in brain and skeletal development in Nfix -deficient mice. Here we show that disruption of Nfix by Cre-recombinase mediated excision of the 2nd exon results in defects in brain development that differ from those seen in Nfia and Nfib KO mice. In particular, complete callosal agenesis is not seen in Nfix -/- mice but rather there appears to be an overabundance of aberrant Pax6 - and doublecortin-positive cells in the lateral ventricles of Nfix -/- mice, increased brain weight, expansion of the cingulate cortex and entire brain along the dorsal ventral axis, and aberrant formation of the hippoc us. On standard lab chow Nfix -/- animals show a decreased growth rate from ~P8 to P14, lose weight from ~P14 to P22 and die at ~P22. If their food is supplemented with a soft dough chow from P10, Nfix -/- animals show a lag in weight gain from P8 to P20 but then increase their growth rate. A fraction of the animals survive to adulthood and are fertile. The weight loss correlates with delayed eye and ear canal opening and suggests a delay in the development of several epithelial structures in Nfix -/- animals. These data show that Nfix is essential for normal brain development and may be required for neural stem cell homeostasis. The delays seen in eye and ear opening and the brain morphology defects appear independent of the nutritional deprivation, as rescue of perinatal lethality with soft dough does not eliminate these defects.
Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo
Publisher: Springer Science and Business Media LLC
Date: 11-2000
DOI: 10.1038/80632
Abstract: The use of gene deletion by homologous recombination to determine gene or protein function has wide application in vertebrate neurobiology. An ideal complement to gene deletion would be subsequent gene replacement to demonstrate re-acquisition of function. Here we used an adenoviral vector to replace the olfactory marker protein (OMP) gene in olfactory receptor neurons of adult OMP-null mice and demonstrated the subsequent re-acquisition of function. Our results show that short-term expression of OMP restores the kinetics of electrophysiological responses of OMP-null mice to those of the control phenotype. This adenoviral-mediated rescue of the OMP-null phenotype is consistent with involvement of OMP in olfactory transduction.
EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex
Publisher: The Company of Biologists
Date: 11-2015
DOI: 10.1242/DEV.119909
Abstract: Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.
Expression of the Netrin-1 receptor, deleted in colorectal cancer (DCC), is largely confined to projecting neurons in the developing forebrain
Publisher: Wiley
Date: 10-01-2000
DOI: 10.1002/(SICI)1096-9861(20000110)416:2<201::AID-CNE6>3.0.CO;2-Z
Abstract: Axon guidance mechanisms are crucial to the development of an integrated nervous system. One family of molecules that may be important in establishing axonal connectivity in mammals is the Netrins, and their putative receptors DCC (deleted in colorectal cancer), Neogenin, and Unc-5. Knockout and mutational analyses of some of these genes have shown that they are critically involved in the development of several specific pathways in the developing brain. However, previous expression analyses of these genes have largely been confined to the developing spinal cord. In the present study, we analyzed the expression of DCC in the developing mouse forebrain. We found that DCC protein is expressed in specific axonal populations projecting from the developing olfactory bulb, neocortex, hippoc us, and epithalamus/habenular complex. In the developing olfactory bulb and neocortex, DCC expression is particularly evident during the targeting phase of axon outgrowth and is then rapidly downregulated. As predicted from the knockout and mutational analyses of this gene, DCC is expressed in axonal commissures, in particular the corpus callosum, hippoc al commissure, and the anterior commissure. In addition, we found that DCC is expressed in the habenular commissure, the fasciculus retroflexus, and the stria medularis. Therefore, this analysis implicates a function for DCC in additional axonal guidance systems not predicted from the knockout and mutational analyses.
Expression of nuclear factor one A and ‐B in the olfactory bulb
Publisher: Wiley
Date: 10-08-2012
DOI: 10.1002/CNE.23081
Abstract: The nuclear factor one (NFI) family of transcription factors consists of four members in vertebrates, NFIA, NFIB, NFIC, and NFIX, which share a highly conserved N-terminal DNA-binding domain. NFI genes are widely expressed in the developing mouse brain, and mouse mutants lacking NFIA, NFIB, or NFIX exhibit developmental deficits in several areas, including the cortex, hippoc us, pons, and cerebellum. Here we analyzed the expression of NFIA and NFIB in the developing and adult olfactory bulb (OB), rostral migratory stream (RMS), and subventricular zone (SVZ). We found that NFIA and NFIB are expressed within these regions during embryonic and postnatal development and in the adult. Immunohistochemical analysis using cell-type-specific markers revealed that migrating neuroblasts in the adult brain express NFI transcription factors, as do astrocytes within the RMS and progenitor cells within the SVZ. Moreover, astrocytes within the OB express NFIA, whereas mitral cells within the OB express NFIB. Taken together these data show that NFIA and NFIB are expressed in both the developing and the adult OB and in the RMS and SVZ, indicative of a regulatory role for these transcription factors in the development of this facet of the olfactory system.
Mutant mouse cerebellum does not provide specific signals for the selective migration and development of transplanted Purkinje cells
Publisher: Elsevier BV
Date: 05-1993
DOI: 10.1016/0304-3940(93)90664-7
Abstract: Embryonic cerebellum transplanted to adult Purkinje cell degenerate mice was assessed for integration and Purkinje cell migration by using the antigenic markers Thy-1 and Leu-4. It was found that the grafted cells migrated into the host's molecular layer, but there was no evidence for specific migration of Purkinje cells. Furthermore, grafted cells were found to form normal cerebellar cyto-architecture only with other grafted cells and not with the host's cells.
Cortical activity emerges in region-specific patterns during early brain development
Publisher: Cold Spring Harbor Laboratory
Date: 19-02-2023
DOI: 10.1101/2023.02.18.529078
Abstract: The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in non-eutherian mammals, as well as when and how they arise during development remain open questions relevant to understand brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer a new approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice), and examined progressively earlier stages of development to determine their onset and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate early events in cortical development. Region-specific patterns of neural activity are present at birth in rodents and are thought to refine synaptic connections during critical periods of cerebral cortex development. Marsupials are born much more immature than rodents, allowing the investigation of how these patterns arise in vivo. We discovered that cortical activity patterns are remarkably similar in marsupial dunnarts and rodents, and that they emerge very early, before cortical neurogenesis is complete. Moreover, they arise from the outset in different patterns specific to somatosensory and visual areas (i.e., patchworks and waves) indicating they may also play evolutionarily conserved roles in cortical regionalization during development.
Loss of Usp9x Disrupts Cortical Architecture, Hippocampal Development and TGF beta-Mediated Axonogenesis
Publisher: Public Library of Science (PLoS)
Date: 05-07-2013
Increased persuadability and credulity in people with corpus callosum dysgenesis
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CORTEX.2022.07.009
Abstract: Corpus callosum dysgenesis is one of the most common congenital neurological malformations. Despite being a clear and identifiable structural alteration of the brain's white matter connectivity, the impact of corpus callosum dysgenesis on cognition and behaviour has remained unclear. Here we build upon past clinical observations in the literature to define the clinical phenotype of corpus callosum dysgenesis better using unadjusted and adjusted group differences compared with a neurotypical s le on a range of social and cognitive measures that have been previously reported to be impacted by a corpus callosum dysgenesis diagnosis. Those with a diagnosis of corpus callosum dysgenesis (n = 22) demonstrated significantly higher persuadability, credulity, and insensitivity to social trickery than neurotypical (n = 86) participants, after controlling for age, sex, education, autistic-like traits, social intelligence, and general cognition. To explore this further, we examined the covariance structure of our psychometric variables using a machine learning algorithm trained on a neurotypical dataset. The algorithm was then used to test whether these dimensions possessed the capability to discriminate between a test-set of neurotypical and corpus callosum dysgenesis participants. After controlling for age and sex, and with Leave-One-Out-Cross-Validation across 250 training-set bootstrapped iterations, we found that participants with a diagnosis of corpus callosum dysgenesis were best classed within dimension space along the same axis as persuadability, credulity, and insensitivity to social trickery, with a mean accuracy of 71.7%. These results have implications for a) the characterisation of corpus callosum dysgenesis, and b) the role of the corpus callosum in social inference.
Mapk/Erk activation in an animal model of social deficits shows a possible link to autism
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Commissure formation in the mammalian forebrain
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.CONB.2007.01.008
Abstract: Commissural formation in the mammalian brain is highly organised and regulated both by the cell-autonomous expression of transcription factors, and by non-cell-autonomous mechanisms including the formation of midline glial structures and their expression of specific axon guidance molecules. These mechanisms channel axons into the correct path and enable the subsequent connection of specific brain areas to their appropriate targets. Several key findings have been made over the past two years, including the discovery of novel mechanisms of action that 'classical' guidance factors such as the Slits, Netrins, and their receptors have in axon guidance. Moreover, novel guidance factors such as members of the Wnt family, and extracellular matrix components such as heparan sulphate proteoglycans, have been shown to be important for mammalian brain commissure formation. Additionally, there have been significant discoveries regarding the role of FGF signalling in the formation of midline glial structures. In this review, we discuss the most recent advances in the field that have contributed to our current understanding of commissural development in the telencephalon.
Diffusion Tensor Magnetic Resonance Imaging and Tract-Tracing Analysis of Probst Bundle Structure in Netrin1- and DCC-Deficient Mice
Publisher: Society for Neuroscience
Date: 26-09-2007
DOI: 10.1523/JNEUROSCI.2787-07.2007
Abstract: In many cases of callosal dysgenesis in both human patients and mouse models, misguided fibers from the cortex form abnormal bilateral, barrel-shaped structures known as Probst bundles. Because little is known about how axons are arranged within these anomalous fiber bundles, understanding this arrangement may provide structural and molecular insights into how axons behave when they are misguided in vivo . Previous studies described these bundles as longitudinal swirls of axons that fail to cross the midline (Ozaki et al., 1987). However, recent studies on human acallosal patients using diffusion tensor magnetic resonance imaging (DTMRI) technology suggest that axons project in an anteroposterior direction within the Probst bundle (Lee et al., 2004 Tovar-Moll et al., 2007). This led us to ask the question, is DTMRI an accurate method for analyzing axonal tracts in regions of high axon overlap and disorganization, or is our current perception of axon arrangement within these bundles inaccurate? Using DTMRI, immunohistochemistry, and carbocyanine dye tract-tracing studies, we analyzed the Probst bundles in both Netrin1 and deleted in colorectal cancer (DCC) mutant mice. Our findings indicate that DTMRI can accurately demonstrate fiber tract orientation and morphology where axons are in ordered arrays such as in the dorsal part of the bundle. In ventral areas, where the axons are disorganized, no coordinated diffusion is apparent via DTMRI. In these regions, a higher-resolution approach such as tract tracing is required. We conclude that in DCC and Netrin1 mutant mice, guidance mechanisms remain in the dorsal part of the tract but are lost ventrally.
Transcriptional control of long-range cortical projections
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.CONB.2018.05.005
Abstract: Long-range projection neurons of the neocortex form the major tracts of the mammalian brain and are crucial for sensory-motor, associative and executive functions. Development of such circuits involves neuronal proliferation, specification and migration, as well as axonal elongation, navigation and targeting, where growing axons encounter multiple guidance cues and integrate these signals to execute guidance decisions. The complexity of axon guidance mechanisms in the formation of long-range neuronal projections has suggested that they might be under control of transcription factors, which are DNA-binding proteins that regulate the expression of downstream genes. Here we discuss recent advances in our understanding of the control of axon guidance by transcriptional regulation, as well as future directions for the elucidation of the mechanisms and pathological relevance of this process.
Axonal pathfinding mechanisms at the cortical midline and in the development of the corpus callosum
Publisher: FapUNIFESP (SciELO)
Date: 12-2002
DOI: 10.1590/S0100-879X2002001200004
Abstract: The corpus callosum is a large fiber tract that connects neurons in the right and left cerebral hemispheres. Agenesis of the corpus callosum (ACC) is associated with a large number of human syndromes but little is known about why ACC occurs. In most cases of ACC, callosal axons are able to grow toward the midline but are unable to cross it, continuing to grow into large swirls of axons known as Probst bundles. This phenotype suggests that in some cases ACC may be due to defects in axonal guidance at the midline. General guidance mechanisms that influence the development of axons include chemoattraction and chemorepulsion, presented by either membrane-bound or diffusible molecules. These molecules are not only expressed by the final target but by intermediate targets along the pathway, and by pioneering axons that act as guides for later arriving axons. Midline glial populations are important intermediate targets for commissural axons in the spinal cord and brain, including the corpus callosum. The role of midline glial populations and pioneering axons in the formation of the corpus callosum are discussed. Finally the differential guidance of the ipsilaterally projecting perforating pathway and the contralaterally projecting corpus callosum is addressed. Development of the corpus callosum involves the coordination of a number of different guidance mechanisms and the probable involvement of a large number of molecules.
Verbal Adynamia and Conceptualization in Partial Rhombencephalosynapsis and Corpus Callosum Dysgenesis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2021
Nuclear factor I gene expression in the developing forebrain
Publisher: Wiley
Date: 2008
DOI: 10.1002/CNE.21645
Abstract: Three members of the Nuclear Factor I (Nfi) gene family of transcription factors Nfia, Nfib, and Nfix are highly expressed in the developing mouse brain. Nfia and Nfib knockout mice display profound defects in the development of midline glial populations and the development of forebrain commissures (das Neves et al. [1999] Proc Natl Acad Sci U S A 96:11946-11951 Shu et al. [2003] J Neurosci 23:203-212 Steele-Perkins et al. [2005] Mol Cell Biol 25:685-698). These findings suggest that Nfi genes may regulate the substrate over which the commissural axons grow to reach targets in the contralateral hemisphere. However, these genes are also expressed in the cerebral cortex and, thus, it is important to assess whether this expression correlates with a cell-autonomous role in cortical development. Here we detail the protein expression of NFIA and NFIB during embryonic and postnatal mouse forebrain development. We find that both NFIA and NFIB are expressed in the deep cortical layers and subplate prenatally and display dynamic expression patterns postnatally. Both genes are also highly expressed in the developing hippoc us and in the diencephalon. We also find that principally neither NFIA nor NFIB are expressed in callosally projecting neurons postnatally, emphasizing the role for midline glial cell populations in commissure formation. However, a large proportion of laterally projecting neurons express both NFIA and NFIB, indicating a possible cell-autonomous role for these transcription factors in corticospinal neuron development. Collectively, these data suggest that, in addition to regulating the formation of axon guidance substrates, these genes also have cell-autonomous roles in cortical development.
Emx and Nfi Genes Regulate Cortical Development and Axon Guidance in the Telencephalon
Publisher: Wiley
Date: 11-01-2008
Growth cone chemotaxis
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.TINS.2007.11.008
Abstract: Wiring up the nervous system depends on the precise guidance of axonal growth cones to their targets. A key mechanism underlying this guidance is chemotaxis, whereby growth cones detect and follow molecular gradients. Although recent work has uncovered many of the molecules involved in this process, the mechanisms underlying chemotactic axon guidance are still unclear. Here we compare growth cones with neutrophils and Dictyostelium discoideum, systems for which a clear conceptual framework for chemotaxis has recently emerged. This analogy suggests particular ways in which the three key steps of directional sensing, polarisation and motility might be implemented in chemotaxing growth cones.
Diffusion MR Microscopy of Cortical Development in the Mouse Embryo
Publisher: Oxford University Press (OUP)
Date: 10-02-2014
Differential neuronal and glial expression of nuclear factor I proteins in the cerebral cortex of adult mice
Publisher: Wiley
Date: 06-06-2017
DOI: 10.1002/CNE.24239
Wiring the Brain: The Biology of Neuronal Guidance
Publisher: Cold Spring Harbor Laboratory
Date: 12-05-2010
The Transcription Factor Gene Nfib Is Essential for both Lung Maturation and Brain Development
Publisher: Informa UK Limited
Date: 2005
Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum
Publisher: Society for Neuroscience
Date: 14-03-2012
DOI: 10.1523/JNEUROSCI.3679-11.2012
Abstract: Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non-neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance.
Retinotectal maps: molecules, models and misplaced data
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0166-2236(99)01469-1
Abstract: The mechanisms underlying the formation of topographic maps in the retinotectal system have long been debated. Recently, members of the Eph and ephrin receptor-ligand family have been found to provide a molecular substrate for one type of mechanism, that of chemospecific gradient matching, as proposed by Sperry. However, experiments over several decades have demonstrated that there is more to map formation than gradient matching. This article briefly reviews the old and new findings, argues that these two types of data must be properly integrated in order to understand map formation fully, and suggests some experimental and theoretical ways to begin this process.
Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.NEUROIMAGE.2020.116868
Abstract: Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or 'agenesis of the corpus callosum') or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.
Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain
Publisher: The Company of Biologists
Date: 06-2006
DOI: 10.1242/DEV.02379
Abstract: The Slit genes encode secreted ligands that regulate axon branching,commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo (Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippoc al commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippoc al and anterior commissures,and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but,instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons (up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice,particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes,some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling.
Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity
Publisher: Springer Science and Business Media LLC
Date: 04-2007
DOI: 10.1038/NRN2107
Abstract: Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 in iduals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.
The glial sling is a migratory population of developing neurons
Publisher: The Company of Biologists
Date: 07-2003
DOI: 10.1242/DEV.00514
Abstract: For two decades the glial sling has been hypothesized to act as a guidance substratum for developing callosal axons. However, neither the cellular nature of the sling nor its guidance properties have ever been clearly identified. Although originally thought to be glioblasts, we show here that the subventricular zone cells forming the sling are in fact neurons. Sling cells label with a number of neuronal markers and display electrophysiological properties characteristic of neurons and not glia. Furthermore, sling cells are continuously generated until early postnatal stages and do not appear to undergo widespread cell death. These data indicate that the sling may be a source of, or migratory pathway for, developing neurons in the rostral forebrain, suggesting additional functions for the sling independent of callosal axon guidance.
The people behind the papers - Peter Kozulin, Rodrigo Suárez, Qiong-Yi Zhao, Linda Richards and Laura Fenlon
Publisher: The Company of Biologists
Date: 02-2022
DOI: 10.1242/DEV.200543
Abstract: The neocortex is unique to mammals and so, for evolutionary studies, researchers have compared eutherians and marsupials. A new paper in Development uncovers key differences in the timing of gene expression changes in the cortical development of the mouse and the similarly sized marsupial, the fat-tailed dunnart. We caught up with the authors from The University of Queensland, Australia, to find out more about their research and their future plans.
Cortical activity emerges in region-specific patterns during early brain development
Publisher: Proceedings of the National Academy of Sciences
Date: 22-05-2023
Abstract: The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex, patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in noneutherian mammals, as well as when and how they arise during development, remain open questions relevant for understanding brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer an approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice) and examined earlier stages of development to determine the onset of these patterns and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate other early events in cortical development.
REGULATION OF NEURAL PRECURSOR DIFFERENTIATION IN THE EMBRYONIC AND ADULT FOREBRAIN
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1440-1681.1995.TB02066.X
Abstract: 1. Precursors form the neuroepithelium of the developing cortex and also from the adult sub-ventricular zone, can be cloned in vitro after stimulation with fibroblast growth factor (FGF)-2 and have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyteprecursor line, Ast-1, or FGF-1. 2. Neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol-lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the PCL gamma pathway. 3. The sequential expression of FGF-2 and FGF-1 within the developing forebrain neuroepithelium fits with the different functions the two FGF play in precursor regulation. 4. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan (HSPG) expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2 however, the differentiation into GFAP positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor beta receptor.
Development of midline glial populations at the corticoseptal boundary
Publisher: Wiley
Date: 08-09-2003
DOI: 10.1002/NEU.10252
Abstract: Three midline glial populations are found at the corticoseptal boundary: the glial wedge (GW), glia within the indusium griseum (IGG), and the midline zipper glia (MG). Two of these glial populations are involved in axonal guidance at the cortical midline, specifically development of the corpus callosum. Here we investigate the phenotypic and molecular characteristics of each population and determine whether they are generated at the same developmental stage. We find that the GW is derived from the radial glial scaffold of the cortex. GW cells initially have long radial processes that extend from the ventricular surface to the pial surface, but by E15 loose their pial attachment and extend only part of the way to the pial surface. Later in development the radial morphology of cells within the GW is replaced by multipolar astrocytes, providing supportive evidence that radial glia can transform into astrocytes. IGG and MG do not have a radial morphology and do not label with the radial glial markers, Nestin and RC2. We conclude that the GW and IGG have different morphological and molecular characteristics and are born at different stages of development. IGG and MG have many phenotypic and molecular characteristics in common, indicating that they may represent a common population of glia that becomes spatially distinct by the formation of the corpus callosum.
Leukaemia inhibitory factor or related factors promote the differentiation of neuronal and astrocytic precursors within the developing murine spinal cord
Publisher: Wiley
Date: 02-1996
DOI: 10.1111/J.1460-9568.1996.TB01213.X
Abstract: Previously we have shown that leukaemia inhibitory factor (LIF) potentiates the development of murine spinal cord neurons in vitro, suggesting that it, or related factors, may play an important regulatory role in neuronal development. We have further investigated this role and show here that the generation of neurons in cultures of embryonic day 10 spinal cord cells is inhibited by antibodies to the beta subunit of the LIF receptor. Since there are more undifferentiated precursors in antibody-treated cultures than in control and LIF-treated cultures, it is concluded that the primary action of LIF, or related molecules, is to promote neuronal differentiation, not precursor survival. In addition, the failure of LIF to support neuronal survival in the period immediately following differentiation suggests that the increased numbers of neurons generated with LIF are not attributable to its neurotrophic action. By selecting neuronal precursors on the basis of their inability to express class 1 major histocompatibility complex molecules, it was shown that LIF acted directly upon these cells and not via an intermediary cell. LIF also appears to be involved in regulating the differentiation of astrocytes, since it increases the number of glial fibrillary protein (GFAP)-positive cells present in the cultures and since the spontaneous production of GFAP-positive cells is blocked by antibodies to the LIF beta receptor. These findings suggest that LIF or related factors promote the differentiation of neural precursors in the spinal cord, but that they are not involved in preferentially promoting precursors down a specific differentiation pathway.
Molecular regulation of the developing commissural plate
Publisher: Wiley
Date: 13-07-2010
DOI: 10.1002/CNE.22445
The spatial and temporal expression patterns of netrin receptors, DCC and neogenin, in the developing mouse retina
Publisher: Elsevier BV
Date: 06-2000
Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human
Publisher: Wiley
Date: 08-09-2004
Comparative mouse brain tractography of diffusion magnetic resonance imaging
Publisher: Elsevier BV
Date: 07-2010
Leukemia inhibitory factor promotes the neuronal development of spinal cord precursors from the neural tube
Publisher: Wiley
Date: 11-1992
Abstract: Recent evidence from our laboratory has shown that leukemia inhibitory factor (LIF) can act early in peripheral nervous system development. We have investigated a potential role of LIF in the developing spinal cord. In explants and dissociated cultures of spinal cord primordium, LIF stimulated a profuse neurite outgrowth. To determine if these effects were related to neuronal differentiation, cells were plated at low cell density and stained for neurofilament. LIF stimulated an increase in the number of newly differentiated neurons, without inducing proliferation of the precursors. Given that LIF has previously reported effects as a cholinergic switching factor for sympathetic neurons, we investigated whether LIF had similar effects in these spinal cord cultures. LIF increased the number of cholinergic neurons in proportion to its overall effect on the stimulation of all neurofilament positive neurons in the culture. These data show that LIF stimulates the generation of spinal cord neurons from their precursors and further implicates a role for LIF in nervous system development.
Fgfr3 regulates development of the caudal telencephalon
Publisher: Wiley
Date: 12-04-2011
DOI: 10.1002/DVDY.22636
Abstract: The fibroblast growth factor receptor 3 (Fgfr3) is expressed in a rostral(low) to caudal(high) gradient in the developing cerebral cortex. Therefore, we hypothesized that Fgfr3 contributes to the correct morphology and connectivity of the caudal cortex. Overall, the forebrain structures appeared normal in Fgfr3(-/-) mice. However, cortical and hippoc al volumes were reduced by 26.7% and 16.3%, respectively. Hypoplasia was particularly evident in the caudo-ventral region of the telencephalon where proliferation was mildly decreased at embryonic day 18.5. Dysplasia of GABAergic neurons in the amygdala and piriform cortex was seen following GAD67 immunohistochemistry. Dye-tracing studies and diffusion magnetic resonance imaging and tractography detected a subtle thalamocortical tract deficit, and significant decreases in the stria terminalis and lateral arms of the anterior commissure. These results indicate the subtle role of Fgfr3 in formation of caudal regions of the telencephalon affecting some brain projections.
PAX6 does not regulate Nfia and Nfib expression during neocortical development
Publisher: Springer Science and Business Media LLC
Date: 29-05-2015
DOI: 10.1038/SREP10668
Abstract: The Nuclear factor I (NFI) family of transcription factors regulates proliferation and differentiation throughout the developing central nervous system. In the developing telencephalon of humans and mice, reduced Nfi expression is associated with agenesis of the corpus callosum and other neurodevelopmental defects. Currently, little is known about how Nfi expression is regulated during early telencephalic development. PAX6, a transcription factor important for telencephalic development, has been proposed as an upstream regulator of Nfi expression in the neocortex. Here we demonstrate that, in the developing neocortex of mice, NFIA and NFIB are endogenously expressed in gradients with high caudo-medial to low rostro-lateral expression and are most highly expressed in the cortical plate. We found that this expression pattern deviates from that of PAX6, suggesting that PAX6 does not drive Nfi expression. This is supported by in vitro reporter assays showing that PAX6 over-expression does not regulate Nfi promoter activity. Similarly, we also found that in the Pax6 Small Eye mutant, no changes in Nfi mRNA or protein expression are observed in the neocortical ventricular zone where PAX6 and the NFIs are expressed. Together these data demonstrate that in mice, PAX6 is not a transcriptional activator of Nfi expression during neocortical development.
Author response: DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
Publisher: eLife Sciences Publications, Ltd
Date: 02-04-2021
Nuclear Factor One Transcription Factors in CNS Development
Publisher: Springer Science and Business Media LLC
Date: 05-12-2008
DOI: 10.1007/S12035-008-8048-6
Abstract: Transcription factors are key regulators of central nervous system (CNS) development and brain function. Research in this area has now uncovered a new key player-the nuclear factor one (NFI) gene family. It has been almost a decade since the phenotype of the null mouse mutant for the nuclear factor one A transcription factor was reported. Nfia null mice display a striking brain phenotype including agenesis of the corpus callosum and malformation of midline glial populations needed to guide axons of the corpus callosum across the midline of the developing brain. Besides NFIA, there are three other NFI family members in vertebrates: NFIB, NFIC, and NFIX. Since generation of the Nfia knockout (KO) mice, KO mice for all other family members have been generated, and defects in one or more organ systems have been identified for all four NFI family members (collectively referred to as NFI here). Like the Nfia KO mice, the Nfib and Nfix KO mice also display a brain phenotype, with the Nfib KO forebrain phenotype being remarkably similar to that of Nfia. Over the past few years, studies have highlighted NFI as a key payer in a variety of CNS processes including axonal outgrowth and guidance and glial and neuronal cell differentiation. Here, we discuss the importance and role of NFI in these processes in the context of several CNS systems including the neocortex, hippoc us, cerebellum, and spinal cord at both cellular and molecular levels.
The DCC receptor regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2020
DOI: 10.1101/2020.08.03.233593
Abstract: The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippoc al commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
International Brain Initiative: An Innovative Framework for Coordinated Global Brain Research Efforts
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.NEURON.2020.01.002
Abstract: The International Brain Initiative (IBI) has been established to coordinate efforts across existing and emerging national and regional brain initiatives. This NeuroView describes how to be involved and the new opportunities for global collaboration that are emerging between scientists, scientific societies, funders, industry, government, and society.
Differential timing of a conserved transcriptional network underlies divergent cortical projection routes across mammalian brain evolution
Publisher: Proceedings of the National Academy of Sciences
Date: 20-04-2020
Abstract: The corpus callosum connects left and right cerebral cortices, integrating sensory-motor and associative functions, and is the largest connection in the human brain. While all mammals have a cerebral cortex, only eutherians evolved a corpus callosum. However, how this occurred remains largely unknown. We compared transcription factors that control subcerebral versus callosal neuron projection fates in eutherians and marsupials and found remarkably high similarity of their gene sequences and functions. However, expression of the callosal gene SATB2 was delayed in mice relative to dunnarts, and premature overexpression was sufficient for reversion to an ancestral-like brain phenotype. Our results suggest that transcriptional heterochrony might have influenced callosal evolution, and that complex traits can originate by differential deployment of existing regulatory genes.
Long-distance aberrant heterotopic connectivity in a mouse strain with a high incidence of callosal anomalies
Publisher: Elsevier BV
Date: 08-2020
De novo generation of neuronal cells from the adult mouse brain
Publisher: Proceedings of the National Academy of Sciences
Date: 15-09-1992
Abstract: Cells of neuronal morphology, expressing the 150- and 200-kDa neurofilament proteins, were generated in vitro from populations of neural cells dissociated from adult (greater than 60-day-old) mouse brain. Most of these neurons arose from iding precursors, as demonstrated by the incorporation of [3H]thymidine during the culture period and autoradiography. Neuronal production was optimal under the conditions in which precursors were initially stimulated with basic fibroblast growth factor and then exposed to medium conditioned by an astrocytic cell line, Ast-1, in serum-free medium. Few, if any, neurons arose in control cultures or in cultures kept in serum and fibroblast growth factor. These results suggest that neuronal precursors exist in the adult mammalian brain, but they require discrete epigenetic signals for their proliferation and differentiation.
Multiple events of gene manipulation via in pouch electroporation in a marsupial model of mammalian forebrain development
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JNEUMETH.2017.09.004
Abstract: The technique of in utero electroporation has been widely used in eutherians, such as mice and rats, to investigate brain development by selectively manipulating gene expression in specific neuronal populations. A major challenge, however, is that surgery is required to access the embryos, affecting animal survival and limiting the number of times it can be performed within the same litter. Marsupials are born at an early stage of brain development as compared to eutherians. Forebrain neurogenesis occurs mostly postnatally, allowing electroporation to be performed while joeys develop attached to the teat. Here we describe the method of in pouch electroporation using the Australian marsupial fat-tailed dunnart (Sminthopsis crassicaudata, Dasyuridae). In pouch electroporation is minimally invasive, quick, successful and anatomically precise. Moreover, as no surgery is required, it can be performed several times in the same in idual, and littermates can undergo independent treatments. As compared to in utero electroporation in rodents, in pouch electroporation in marsupials offers unprecedented opportunities to study brain development in a minimally invasive manner. Continuous access to developing joeys during a protracted period of cortical development allows multiple and independent genetic manipulations to study the interaction of different systems during brain development. In pouch electroporation in marsupials offers an excellent in vivo assay to study forebrain development and evolution. By combining developmental, functional and comparative approaches, this system offers new avenues to investigate questions of biological and medical relevance, such as the precise mechanisms of brain wiring and the organismic and environmental influences on neural circuit formation.
Identification of candidate genes at the corticoseptal boundary during development
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.MODGEP.2005.11.004
Abstract: Cortical midline glia are critical to the formation of the corpus callosum during development. The glial wedge is a population of midline glia that is located at the corticoseptal boundary and expresses repulsive/growth-inhibitory molecules that guide callosal axons as they cross the midline. The glial wedge are the first cells within the cortex to express GFAP and thus may express molecules specific for glial maturation. The corticoseptal boundary is a genetically defined boundary between the cingulate cortex (dorsal telencephalon) and the septum (ventral telencephalon). The correct dorso-ventral position of this boundary is vital to the formation of both the glial wedge and the corpus callosum. Our aim was to identify genes expressed specifically within the glial wedge that might be involved in either glial differentiation, formation of the corticoseptal boundary or development of the corpus callosum. To identify such genes we have performed a differential display PCR screen comparing RNA isolated from the glial wedge with RNA isolated from control tissues such as the neocortex and septum, of embryonic day 17 mouse brains. Using 200 different combinations of primers, we identified and cloned 67 distinct gene fragments. In situ hybridization analysis confirmed the differential expression of many of the genes, and showed that clones G24F3, G39F8 and transcription factor LZIP have specific expression patterns in the telencephalon of embryonic and postnatal brains. An RNase Protection Assay (RPA) revealed that the expression of G39F8, G24F3 and LZIP increase markedly in the telencephalon at E16 and continue to be expressed until at least P0, during the period when the corpus callosum is forming.
Related Organisations
The University Of Queensland Queensland Brain Institute
Location: Australia
Washington University In St. Louis School Of Medicine
Location: United States of America
The University Of Melbourne, Walter And Eliza Hall Institute Of Medical Research
Location: Australia
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