ORCID Profile
0000-0002-0378-7078
Current Organisation
Remotely Consulting
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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)
Cellular Nervous System | Central Nervous System | Pharmacology and Pharmaceutical Sciences | Pharmaceutical Sciences | Biomaterials | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Cell Development, Proliferation and Death | Neurosciences
ANZSRC Socio-Economic Objective (SEO)
Human Biological Preventatives (e.g. Vaccines) | Expanding Knowledge in the Biological Sciences | Human Diagnostics | Human Pharmaceutical Treatments (e.g. Antibiotics) |
Related Links
Publications
Reinforcing the association between distal 1q CNVs and structural brain disorder: A case of a complex 1q43-q44 CNV and a review of the literature
Publisher: Wiley
Date: 07-02-2016
DOI: 10.1002/AJMG.B.32427
Abstract: Copy Number Variations (CNVs) comprising the distal 1q region 1q43-q44 are associated with neurological impairments, structural brain disorder, and intellectual disability. Here, we report an extremely rare, de novo case of a 1q43-q44 deletion with an adjacent duplication, associated with severe seizures, microcephaly, agenesis of the corpus callosum, and pachygyria, a consequence of defective neuronal migration disorder. We conducted a literature survey to find that our patient is only the second case of such a 1q43-q44 CNV ever to be described. Our data support an association between 1q43-q44 deletions and microcephaly, as well as an association between 1q43-q44 duplications and macrocephaly. We compare and contrast our findings with previous studies reporting on critical 1q43-q44 regions and their constituent genes associated with seizures, microcephaly, and corpus callosum abnormalities [Ballif et al., 2012 Hum Genet 131:145-156 Nagamani et al., 2012 Eur J Hum Genet 20:176-179]. Taken together, our study reinforces the association between 1q43-q44 CNVs and brain disorder.
De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
Publisher: Elsevier BV
Date: 06-2016
The Zinc Finger Transcription Factor RP58 Negatively Regulates Rnd2 for the Control of Neuronal Migration During Cerebral Cortical Development
Publisher: Oxford University Press (OUP)
Date: 10-2013
Abstract: The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009 Xiang et al. 2011 Baubet et al. 2012 Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex. Loss of RP58 within the embryonic cortex also leads to elevated mRNA for Rnd2, a member of the Rnd family of atypical RhoA-like GTPase proteins important for cortical neuron migration (Heng et al. 2008). Mechanistically, RP58 represses transcription of Rnd2 via binding to a 3'-regulatory enhancer in a sequence-specific fashion. Using reporter assays, we found that RP58 repression of Rnd2 is competed by proneural basic helix-loop-helix transcriptional activators. Finally, our rescue experiments revealed that negative regulation of Rnd2 by RP58 was important for cortical cell migration in vivo. Taken together, these studies demonstrate that RP58 is a key player in the transcriptional control of cell migration in the developing cerebral cortex.
Brinp1 −/− mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
Blood–brain distribution of morphine‐6‐glucuronide in sheep
Publisher: Wiley
Date: 11-2006
Neurogenin 2 controls cortical neuron migration through regulation of Rnd2
Publisher: Springer Science and Business Media LLC
Date: 06-08-2008
DOI: 10.1038/NATURE07198
Abstract: Motility is a universal property of newly generated neurons. How cell migration is coordinately regulated with other aspects of neuron production is not well understood. Here we show that the proneural protein neurogenin 2 (Neurog2), which controls neurogenesis in the embryonic cerebral cortex, directly induces the expression of the small GTP-binding protein Rnd2 (ref. 3) in newly generated mouse cortical neurons before they initiate migration. Rnd2 silencing leads to a defect in radial migration of cortical neurons similar to that observed when the Neurog2 gene is deleted. Remarkably, restoring Rnd2 expression in Neurog2-mutant neurons is sufficient to rescue their ability to migrate. Our results identify Rnd2 as a novel essential regulator of neuronal migration in the cerebral cortex and demonstrate that Rnd2 is a major effector of Neurog2 function in the promotion of migration. Thus, a proneural protein controls the complex cellular behaviour of cell migration through a remarkably direct pathway involving the transcriptional activation of a small GTP-binding protein.
Two lines of transgenic mice expressing cre-recombinase exhibit increased seizure susceptibility
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.EPLEPSYRES.2012.10.005
Abstract: Conditional mouse models based on the Cre-recombinase (Cre)-loxP method are a powerful tool for determining the spatial and temporal function of genes in neuroscience research. The Emx1-Cre conditional model is designed to drive Cre expression in a predominantly excitatory neuron specific manner and the Dlx5/6-Cre mouse expresses Cre predominantly in cortical inhibitory neurons. The mouse models expressing the Cre transgene are healthy, active and have no overt behavioural or brain histological phenotypes. Subcutaneous pentylenetetrazol (scPTZ) is a proconvulsant frequently used to probe neuronal network excitability. In both the Emx1-Cre and Dlx5/6-Cre conditional mouse models the latency to scPTZ-induced seizures was significantly shorter than for their wild-type littermates. This shows that mouse models carrying the Cre transgene alone can have significant behavioural phenotypes. This may act as a confound to the interpretation of data obtained from crosses with loxP-flanked targets especially in the context of epilepsy phenotypes. These data highlight that appropriate control experiments that compare wild-type mice to those that carry the cre-transgene but not the loxP-flanked target are essential when using this method.
14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders
Publisher: Springer Science and Business Media LLC
Date: 24-07-2015
DOI: 10.1038/SREP12434
Abstract: Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ −/− mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ −/− phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ −/− BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippoc us. In contrast to our previous analyses, 14-3-3ζ −/− BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippoc us and ventricle and cognitive defects such as hippoc al-dependent learning and memory.
Studying Disease-Associated UBE3A Missense Variants Using Enhanced Sampling Molecular Simulations
Publisher: American Chemical Society (ACS)
Date: 11-07-2022
Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie?
Publisher: BMJ
Date: 29-07-2015
DOI: 10.1136/BJSPORTS-2014-094546
Abstract: Subepicardial delayed gadolinium enhancement (DGE) patches without underlying cardiomyopathy is poorly understood. It is often reported as the result of prior silent myocarditis. Its prognostic relevance in asymptomatic athletes is unknown therefore, medical clearance for competitive sports participation is debated. This case series aims to relate this pattern of DGE in athletes to outcome. We report on seven young asymptomatic athletes with isolated subepicardial DGE detected during workup of abnormalities on their regular screening examination, that is, pathological T-wave inversions on ECG (n=4) or ventricular arrhythmias on exercise test (n=3). All underwent a comprehensive initial investigation in order to assess left ventricular (LV) function at rest and exercise (exercise cardiac MRI and/or exercise echocardiography) and occurrence of arrhythmias (exercise test, 24 h-ECG Holter, electrophysiological study). All underwent a careful follow-up with biannual evaluation. All athletes had extensive subepicardial DGE (12.0±4.8% of LV mass), predominantly in the lateral wall. Three athletes had non-sustained ventricular arrhythmias, whereas two of them had LV ejection fraction <50% at rest with no contractile reserve at exercise. During a follow-up of 3.0±1.5 years in the four remaining athletes, two had symptomatic ventricular tachycardia and one demonstrated progressive LV dysfunction. Hence, six of seven athletes had to be excluded from competitive sports participation. Isolated large areas of subepicardial DGE in an asymptomatic athlete are not benign and require a careful evaluation at exercise and a strict follow-up. These findings question whether extreme exercise during silent myocarditis may facilitate fibrosis generation and adverse remodelling.
Molecular mechanisms of projection neuron production and maturation in the developing cerebral cortex
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.SEMCDB.2009.04.003
Abstract: The cerebral cortex is a brain structure unique to mammals and highly adapted to process complex information. Through multiple developmental steps, the cerebral cortex is assembled as a huge ersity of neurons comprising a complex laminar structure, and with both local and long-distance connectivity within the nervous system. Key processes must take place during its construction, including: (i) regulation of the correct number of neurons produced by progenitor cells, (ii) temporal and spatial generation of neuronal ersity, and (iii) control of neuron migration and laminar positioning as well as terminal differentiation within the mature cortex. Here, we seek to highlight recent cellular and molecular findings underlying these sequential steps of neurogenesis, cell fate specification and migration during cortical development, with particular emphasis on cortical projection neurons.
Neurotransmitters regulate cell migration in the telencephalon
Publisher: Wiley
Date: 08-2007
DOI: 10.1111/J.1460-9568.2007.05694.X
Abstract: The complex cytoarchitectonic organization of the adult mammalian telencephalon reflects the elaborate patterns of cell migration that contribute to its generation. The migration by neurons in the CNS can broadly be ided into two categories: radial and tangential. Experimental observations in the telencephalon have shown that glutamatergic projection neurons are born in the progenitor compartment of the dorsal telencephalon and migrate radially to integrate the cortical plate, whereas most gamma-aminobutyric acid (GABA)ergic interneurons are generated in the ganglionic eminences and navigate through multiple tangential paths to settle into distinct telencephalic structures. Despite progress towards the understanding of the genetic determinants that specify the fate of neuronal progenitors, much remains unknown about the mechanisms that direct their migration into specific regions of the telencephalon. Interestingly, besides their function in synaptic transmission, neurotransmitters have been shown to promote several developmental processes that contribute to the establishment and maintenance of the CNS. In this respect, recent studies have highlighted a role for neurotransmitters through activation of their receptors in regulating cell migration in the telencephalon. This review summarizes and discusses the growing body of literature implicating neurotransmitters and their cognate receptors as part of a complex molecular machinery that regulate the migration of immature neurons in the telencephalon during development and in adulthood.
Molecular layers underlying cytoskeletal remodelling during cortical development
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.TINS.2009.09.003
Abstract: During neural development, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling to facilitate the sequential steps of neurogenesis, cell migration and terminal differentiation. It is clear from studying the mechanisms that precipitate these functions that different configurations of the cytoskeleton prefigure the correct execution of each step and define cohorts of proteins the functions of which are indispensable for the control of neuronal migration but not terminal differentiation. These combinatorial protein functions are also predetermined by regulated gene expression and the precise subcellular localisation of their protein products. Here, we expand on this view in the context of recent data on how the cytoskeleton is regulated during the maturation of cortical neurons within the developing brain.
Brain-Enriched Coding and Long Non-coding RNA Genes Are Overrepresented in Recurrent Neurodevelopmental Disorder CNVs.
Publisher: Elsevier BV
Date: 10-2020
Understanding the impact of ZBTB18 missense variation on transcription factor function in neurodevelopment and disease
Publisher: Wiley
Date: 18-02-2022
DOI: 10.1111/JNC.15572
Abstract: Mutations to genes that encode DNA‐binding transcription factors (TFs) underlie a broad spectrum of human neurodevelopmental disorders. Here, we highlight the pathological mechanisms arising from mutations to TF genes that influence the development of mammalian cerebral cortex neurons. Drawing on recent findings for TF genes including ZBTB18 , we discuss how functional missense mutations to such genes confer non‐native gene regulatory actions in developing neurons, leading to cell‐morphological defects, neuroanatomical abnormalities during foetal brain development and functional impairment. Further, we discuss how missense variation to human TF genes documented in the general population endow quantifiable changes to transcriptional regulation, with potential cell biological effects on the temporal progression of cerebral cortex neuron development and homeostasis. We offer a systematic approach to investigate the functional impact of missense variation in brain TFs and define their direct molecular and cellular actions in foetal neurodevelopment, tissue homeostasis and disease states. image
COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression
Publisher: The Company of Biologists
Date: 11-2011
DOI: 10.1242/DEV.068031
Abstract: During corticogenesis, late-born callosal projection neurons (CPNs) acquire their laminar position through glia-guided radial migration and then undergo final differentiation. However, the mechanisms controlling radial migration and final morphology of CPNs are poorly defined. Here, we show that in COUP-TFI mutant mice CPNs are correctly specified, but are delayed in reaching the cortical plate and have morphological defects during migration. Interestingly, we observed that the rate of neuronal migration to the cortical plate normally follows a low-rostral to high-caudal gradient, similar to that described for COUP-TFI. This gradient is strongly impaired in COUP-TFI–/– brains. Moreover, the expression of the Rho-GTPase Rnd2, a modulator of radial migration, is complementary to both these gradients and strongly increases in the absence of COUP-TFI function. We show that COUP-TFI directly represses Rnd2 expression at the post-mitotic level along the rostrocaudal axis of the neocortex. Restoring correct Rnd2 levels in COUP-TFI–/– brains cell-autonomously rescues neuron radial migration and morphological transitions. We also observed impairments in axonal elongation and dendritic arborization of COUP-TFI-deficient CPNs, which were rescued by lowering Rnd2 expression levels. Thus, our data demonstrate that COUP-TFI modulates late-born neuron migration and favours proper differentiation of CPNs by finely regulating Rnd2 expression levels.
The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NCB1727
The role of class I HLH genes in neural development - Have they been overlooked?
Publisher: Wiley
Date: 13-06-2003
DOI: 10.1002/BIES.10299
Abstract: Helix-loop-helix (HLH) genes encode for transcription factors affecting a whole variety of developmental programs, including neurogenesis. At least seven functional classes (denoted I to VII) of HLH genes exist, (1) with subclass members exhibiting homo- and heterodimerisation for proper DNA binding and transcriptional regulation of downstream target genes. In the developing nervous system, members of class II, V and VI have been most extensively studied concerning their roles in neural programming. In contrast, the function of class I proteins (such as E12 and E47) is poorly defined and the orthodox view relegates them to general dimerisation duties that are necessary for the activity of the other classes. However, closer scrutiny of the spatiotemporal expression patterns of class I factors, combined with recent biochemical evidence, would suggest that class I proteins possess specific functions during early neural differentiation. This essay supports this possibility, in addition to putting forward the hypothesis that, outside their general dimerisation activity, class I genes have independent roles in regulating neurogenesis.
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
Coupling of cell migration with neurogenesis by proneural bHLH factors
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2006
Abstract: After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic helix-loop-helix (bHLH) transcription factors not only initiate neuronal differentiation but also potentiate cell migration. Mechanistically, proneural bHLH factors regulate the expression of genes critically involved in migration, including down-regulation of RhoA small GTPase and up-regulation of doublecortin and p35, which, in turn, modulate the actin and microtubule cytoskeleton assembly and enable newly generated neurons to migrate. In addition, we report that several DNA-binding-deficient proneural genes that fail to initiate neuronal differentiation still activate migration, whereas a different mutation of a proneural gene that causes a failure in initiating cell migration still leads to robust neuronal differentiation. Collectively, these data suggest that transcription programs for neurogenesis and migration are regulated by bHLH factors through partially distinct mechanisms.
Cloning and characterization of GRIPE, a novel interacting partner of the transcription factor E12 in developing mouse forebrain
Publisher: Elsevier BV
Date: 11-2002
A review of structural brain abnormalities in Pallister-Killian syndrome.
Publisher: Wiley
Date: 09-12-2017
DOI: 10.1002/MGG3.351
Perturbations in cortical development and neuronal network excitability arising from prenatal exposure to benzodiazepines in mice
Publisher: Wiley
Date: 04-03-2013
DOI: 10.1111/EJN.12167
Abstract: During brain development, many factors influence the assembly and final positioning of cortical neurons, and this process is essential for proper circuit formation and normal brain function. Among many important extrinsic factors that guide the maturation of embryonic cortical neurons, the secreted neurotransmitter GABA has been proposed to influence both their migratory behaviour and their terminal differentiation. The full extent of the short-term and long-term changes in brain patterning and function caused by modulators of the GABA system is not known. In this study, we specifically investigated whether diazepam, a commonly used benzodiazepine that modulates the GABAA receptor, alters neuronal positioning in vivo, and whether this can lead to lasting effects on brain function. We found that fetal exposure to diazepam did not change cell positioning within the embryonic day (E)14.5 mouse cerebral cortex, but significantly altered neuron positioning within the E18.5 cortex. In adult mice, diazepam treatment affected the distribution of cortical interneurons that express parvalbumin or calretinin, and also led to a decrease in the numbers of calretinin-expressing interneurons. In addition, we observed that neonatal exposure to diazepam altered the sensitivity of mice to a proconvulsant challenge. Therefore, exposure of the fetal brain to benzodiazepines has consequences for the positioning of neurons and cortical network excitability.
General population ZBTB18 missense variants influence DNA binding and transcriptional regulation.
Publisher: Hindawi Limited
Date: 15-07-2020
DOI: 10.1002/HUMU.24069
Rp58 and p27kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities
Publisher: Elsevier BV
Date: 12-2012
Infantile Neurodegenerative Disorder Associated with Mutations inTBCD, an Essential Gene in the Tubulin Heterodimer Assembly Pathway
Publisher: Oxford University Press (OUP)
Date: 29-08-2016
DOI: 10.1093/HMG/DDW292
Atypical nested 22q11.2 duplications between LCR 22B and LCR 22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance
Publisher: Wiley
Date: 04-01-2019
DOI: 10.1002/MGG3.507
Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons
Publisher: Springer Science and Business Media LLC
Date: 11-03-2016
WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.
Publisher: The Company of Biologists
Date: 2012
DOI: 10.1242/JCS.107326
Abstract: The impact of aberrant centrosomes/spindles on asymmetric cell ision in embryonic development indicates the tight regulation of bipolar spindle formation and positioning for mitotic progression and cell fate determination. WD40-repeat protein 62 (WDR62) was recently identified as a spindle pole protein linked to the neurodevelopmental defect of microcephaly but its roles in mitosis have not been defined. We report here that the in utero electroporation of neuroprogenitor cells with WDR62 siRNAs induced their cell cycle exit and reduced their proliferative capacity. In cultured cells, we demonstrated cell cycle-dependent accumulation of WDR62 at the spindle pole during mitotic entry that persisted until metaphase-anaphase transition. Utilizing siRNA-depletion, we revealed WDR62 function in stabilizing the mitotic spindle specifically during metaphase. WDR62 loss resulted in spindle orientation defects, decreased the integrity of centrosomes displaced from the spindle pole and delayed mitotic progression. Additionally, we revealed JNK phosphorylation of WDR62 was required for maintaining metaphase spindle organization during mitosis. Our study provides the first functional characterization of WDR62 and has revealed requirements for JNK/WDR62-signalling in mitotic spindle regulation that may be involved in coordinating neurogenesis.
Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function.
Publisher: Frontiers Media SA
Date: 23-11-2018
Proneural proteins and the development of the cerebral cortex
Publisher: Springer Japan
Date: 2013
Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3
Publisher: Wiley
Date: 12-12-2016
DOI: 10.1002/ANA.24502
Abstract: We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated in iduals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression
Publisher: The Company of Biologists
Date: 02-2018
DOI: 10.1242/DEV.155689
Abstract: Our understanding of the transcriptional programme underpinning adult hippoc al neurogenesis is incomplete. In mice, under basal conditions, adult hippoc al neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippoc al neuroblasts. Conditional ablation of Nfix from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following Nfix deletion. Remarkably, when Nfix is deleted specifically from intermediate progenitor cells and neuroblasts using a Dcx-creERT2 driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippoc al stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures.
Phosphorylation of Neurogenin2 Specifies the Migration Properties and the Dendritic Morphology of Pyramidal Neurons in the Neocortex
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.NEURON.2005.08.032
Abstract: The molecular mechanisms specifying the dendritic morphology of different neuronal subtypes are poorly understood. Here we demonstrate that the bHLH transcription factor Neurogenin2 (Ngn2) is both necessary and sufficient for specifying the dendritic morphology of pyramidal neurons in vivo by specifying the polarity of its leading process during the initiation of radial migration. The ability of Ngn2 to promote a polarized leading process outgrowth requires the phosphorylation of a single tyrosine residue at position 241, an event that is neither involved in Ngn2 direct transactivation properties nor its proneural function. Interestingly, the migration defect observed in the Ngn2 knockout mouse and in progenitors expressing the Ngn2(Y241F) mutation can be rescued by inhibiting the activity of the small-GTPase RhoA in cortical progenitors. Our results demonstrate that Ngn2 coordinates the acquisition of the radial migration properties and the unipolar dendritic morphology characterizing pyramidal neurons through molecular mechanisms distinct from those mediating its proneural activity.
TUBB5 and its disease-associated mutations influence the terminal differentiation and dendritic spine densities of cerebral cortical neurons
Publisher: Oxford University Press (OUP)
Date: 15-05-2014
DOI: 10.1093/HMG/DDU238
Abstract: The microtubule cytoskeleton is critical for the generation and maturation of neurons in the developing mammalian nervous system. We have previously shown that mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities in humans. While it is known that TUBB5 is necessary for the proper generation and migration of neurons, little is understood of the role it plays in neuronal differentiation and connectivity. Here, we report that perturbations to TUBB5 disrupt the morphology of cortical neurons, their neuronal complexity, axonal outgrowth, as well as the density and shape of dendritic spines in the postnatal murine cortex. The features we describe are consistent with defects in synaptic signaling. Cellular-based assays have revealed that TUBB5 substitutions have the capacity to alter the dynamic properties and polymerization rates of the microtubule cytoskeleton. Together, our studies show that TUBB5 is essential for neuronal differentiation and dendritic spine formation in vivo, providing insight into the underlying cellular pathology associated with TUBB5 disease states.
Structure-Based Approaches to Classify the Functional Impact of ZBTB18 Missense Variants in Health and Disease.
Publisher: American Chemical Society (ACS)
Date: 23-02-2021
p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2006
DOI: 10.1101/GAD.377106
Abstract: The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27 Kip1 plays an important role in neurogenesis in the mouse cerebral cortex by promoting the differentiation and radial migration of cortical projection neurons. Importantly, these two functions of p27 Kip1 involve distinct activities, which are independent of its role in cell cycle regulation. p27 Kip1 promotes neuronal differentiation by stabilizing Neurogenin2 protein, an activity carried by the N-terminal half of the protein. p27 Kip1 promotes neuronal migration by blocking RhoA signaling, an activity that resides in its C-terminal half. Thus, p27 Kip1 plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.
Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex.
Publisher: Hindawi Limited
Date: 03-07-2019
DOI: 10.1002/HUMU.23803
Abstract: The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.
RP58 Regulates the Multipolar-Bipolar Transition of Newborn Neurons in the Developing Cerebral Cortex
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.CELREP.2013.01.012
Abstract: Accumulating evidence suggests that many brain diseases are associated with defects in neuronal migration, suggesting that this step of neurogenesis is critical for brain organization. However, the molecular mechanisms underlying neuronal migration remain largely unknown. Here, we identified the zinc-finger transcriptional repressor RP58 as a key regulator of neuronal migration via multipolar-to-bipolar transition. RP58(-/-) neurons exhibited severe defects in the formation of leading processes and never shifted to the locomotion mode. Cre-mediated deletion of RP58 using in utero electroporation in RP58(flox/flox) mice revealed that RP58 functions in cell-autonomous multipolar-to-bipolar transition, independent of cell-cycle exit. Finally, we found that RP58 represses Ngn2 transcription to regulate the Ngn2-Rnd2 pathway Ngn2 knockdown rescued migration defects of the RP58(-/-) neurons. Our findings highlight the critical role of RP58 in multipolar-to-bipolar transition via suppression of the Ngn2-Rnd2 pathway in the developing cerebral cortex.
Proneural Transcription Factors Regulate Different Steps of Cortical Neuron Migration through Rnd-Mediated Inhibition of RhoA Signaling
Publisher: Elsevier BV
Date: 03-2011
Further evidence for distinct traits associated with RBM10 missense variants
Publisher: Wiley
Date: 29-05-2022
DOI: 10.1111/CGE.14163
Abstract: A case of a missense RBM10 variant in an adult with mild to moderate intellectual disability.
Insights into the Biology and Therapeutic Applications of Neural Stem Cells
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/9745315
Abstract: The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the ersity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease.
The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome
Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
DOI: 10.1038/SREP29514
Abstract: Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91 , Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate β-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter β-catenin signalling in vitro as well as in vivo . Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome.
Quantitative neurogenetics: applications in understanding disease.
Publisher: Portland Press Ltd.
Date: 20-07-2021
DOI: 10.1042/BST20200732
Abstract: Neurodevelopmental and neurodegenerative disorders (NNDs) are a group of conditions with a broad range of core and co-morbidities, associated with dysfunction of the central nervous system. Improvements in high throughput sequencing have led to the detection of putative risk genetic loci for NNDs, however, quantitative neurogenetic approaches need to be further developed in order to establish causality and underlying molecular genetic mechanisms of pathogenesis. Here, we discuss an approach for prioritizing the contribution of genetic risk loci to complex-NND pathogenesis by estimating the possible impacts of these loci on gene regulation. Furthermore, we highlight the use of a tissue-specificity gene expression index and the application of artificial intelligence (AI) to improve the interpretation of the role of genetic risk elements in NND pathogenesis. Given that NND symptoms are associated with brain dysfunction, risk loci with direct, causative actions would comprise genes with essential functions in neural cells that are highly expressed in the brain. Indeed, NND risk genes implicated in brain dysfunction are disproportionately enriched in the brain compared with other tissues, which we refer to as brain-specific expressed genes. In addition, the tissue-specificity gene expression index can be used as a handle to identify non-brain contexts that are involved in NND pathogenesis. Lastly, we discuss how using an AI approach provides the opportunity to integrate the biological impacts of risk loci to identify those putative combinations of causative relationships through which genetic factors contribute to NND pathogenesis.
Correction to: Rp58 and p27kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
Erratum: The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein (Nature Cell Biology (2008) vol. 10 (643-653))
Publisher: Springer Science and Business Media LLC
Date: 06-2009
DOI: 10.1038/NCB0609-684
Mutations of vasopressin receptor 2 including novel L312S have differential effects on trafficking
Publisher: The Endocrine Society
Date: 08-2016
DOI: 10.1210/ME.2016-1002
Related Organisations
National Institute For Medical Research
Location: United Kingdom of Great Britain and Northern Ireland
Florey Institute Of Neuroscience And Mental Health
Location: Australia
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