ORCID Profile
0000-0001-9712-4082
Current Organisation
Peter MacCallum Cancer Centre
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Biochemistry and Cell Biology | Cell Development, Proliferation and Death | Developmental Genetics (incl. Sex Determination) | Gene Expression (incl. Microarray and other genome-wide approaches) | Bioinformatics | Neurogenetics
Expanding Knowledge in the Biological Sciences | Nervous System and Disorders |
Publisher: EMBO
Date: 11-04-2023
Abstract: Dedifferentiation is the reversion of mature cells to a stem cell‐like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic neural stem cells (NSCs). Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed. Here, we show that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo appropriate temporal progression by constantly expressing mid‐temporal transcription factor(tTF), Sloppy‐paired 1/2 (Slp). Consequently, this resulted in impaired terminal differenation and generated an excess of Twin of eyeless (Toy)‐positive neurons at the expense of Reversed polarity (Repo)‐positive glial cells. Preference for a mid‐temporal fate in these ectopic NSCs is concordant with an enriched binding of Dpn at mid‐tTF loci and a depletion of Dpn binding at early‐ and late‐tTF loci. Retriggering the temporal series via manipulation of the temporal series or cell cycle is sufficient to reinstate neuronal ersity and timely termination.
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.CELL.2008.03.034
Abstract: The timing mechanisms responsible for terminating cell proliferation toward the end of development remain unclear. In the Drosophila CNS, in idual progenitors called neuroblasts are known to express a series of transcription factors endowing daughter neurons with different temporal identities. Here we show that Castor and Seven-Up, members of this temporal series, regulate key events in many different neuroblast lineages during late neurogenesis. First, they schedule a switch in the cell size and identity of neurons involving the targets Chinmo and Broad Complex. Second, they regulate the time at which neuroblasts undergo Prospero-dependent cell-cycle exit or Reaper/Hid/Grim-dependent apoptosis. Both types of progenitor termination require the combined action of a late phase of the temporal series and indirect feedforward via Castor targets such as Grainyhead and Dichaete. These studies identify the timing mechanism ending CNS proliferation and reveal how aging progenitors transduce bursts of transcription factors into long-lasting changes in cell proliferation and cell identity.
Publisher: Cold Spring Harbor Laboratory
Date: 24-03-2023
DOI: 10.1101/2023.03.20.532714
Abstract: Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, have the ability to regenerate PRs efficiently and restore functional vision. Upon injury, mature Müller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 ( her6 ) negatively regulates of PR production by regulating the rate of cell isions in the MG-derived progenitors. prospero homeobox 1 ( prox1 ) is expressed in differentiated PRs, and likely promotes PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1 is precociously upregulated in the PRs, to promote PR differentiation conversely, loss of Prox1 also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other, and may be exploited to promote human retinal regeneration and vision recovery.
Publisher: EMBO
Date: 10-03-2021
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 15-03-2013
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2023
DOI: 10.1101/2023.06.23.546217
Abstract: Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle s les, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homolog ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.CELL.2011.06.040
Abstract: Developing animals survive periods of starvation by protecting the growth of critical organs at the expense of other tissues. Here, we use Drosophila to explore the as yet unknown mechanisms regulating this privileged tissue growth. As in mammals, we observe in Drosophila that the CNS is more highly spared than other tissues during nutrient restriction (NR). We demonstrate that anaplastic lymphoma kinase (Alk) efficiently protects neural progenitor (neuroblast) growth against reductions in amino acids and insulin-like peptides during NR via two mechanisms. First, Alk suppresses the growth requirement for amino acid sensing via Slimfast/Rheb/TOR complex 1. And second, Alk, rather than insulin-like receptor, primarily activates PI3-kinase. Alk maintains PI3-kinase signaling during NR as its ligand, Jelly belly (Jeb), is constitutively expressed from a glial cell niche surrounding neuroblasts. Together, these findings identify a brain-sparing mechanism that shares some regulatory features with the starvation-resistant growth programs of mammalian tumors.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S1534-5807(03)00263-6
Abstract: It is generally held that vertebrate muscle precursors depend totally on environmental cues for their development. We show that instead, somites are predisposed toward a particular myogenic program. This predisposition depends on the somite's axial identity: when flank somites are transformed into limb-level somites, either by shifting somitic boundaries with FGF8 or by overexpressing posterior Hox genes, they readily activate the program typical for migratory limb muscle precursors. The intrinsic control over myogenic programs can only be overridden by FGF4 signals provided by the apical ectodermal ridge of a developing limb.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2016
DOI: 10.1007/S00018-016-2144-Y
Abstract: The ability to maintain cells in a differentiated state and to prevent them from reprogramming into a multipotent state has recently emerged as a central theme in neural development as well as in oncogenesis. In the developing central nervous system (CNS) of the fruit fly Drosophila, several transcription factors were recently identified to be required in postmitotic cells to maintain differentiation, and in their absence, mature neurons undergo dedifferentiation, giving rise to proliferative neural stem cells and ultimately to tumor growth. In this review, we will highlight the current understanding of dedifferentiation and cell plasticity in the Drosophila CNS.
Publisher: Springer Science and Business Media LLC
Date: 1998
Publisher: Springer Berlin Heidelberg
Date: 2002
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.CONB.2009.12.005
Abstract: Neural stem and progenitor cells generate the central nervous system (CNS) in organisms as erse as insects and mammals. In Drosophila, multipotent asymmetrically iding progenitors called neuroblasts produce neurons and glia throughout the developing CNS. Nevertheless, the time-windows of mitotic activity, the ision modes, the termination mechanisms and the lineage sizes of in idual neuroblasts all vary considerably from region-to-region. Recent studies shed light on some of the mechanisms underlying this neuroblast ersity and, in particular, how proliferation is boosted in two brain regions. In the central brain, some specialised neuroblasts generate intermediate neural progenitors that can each ide multiple times, thus increasing overall lineage size. In the optic lobe, an alternative expansion strategy involves symmetrically iding neuroepithelial cells generating large numbers of asymmetrically iding neuroblasts. Evidence is also emerging for a cell-intrinsic timer that alters the properties of each neuroblast with increasing developmental age. The core mechanism corresponds to a series of transcription factors that coordinates temporal changes in neuronal/glial identity with transitions in neuroblast cell-cycle speed, entry into quiescence and, ultimately, with termination.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 27-08-2020
DOI: 10.1002/WDEV.394
Abstract: Studies in model organisms have demonstrated that extensive communication occurs between distant organs both during development and in diseases such as cancer. Organs communicate with each other to coordinate growth and reach the correct size, while the fate of tumor cells depend on the outcome of their interaction with the immune system and peripheral tissues. In this review, we outline recent studies in Drosophila , which have enabled an improved understanding of the complex crosstalk between organs in the context of both organismal and tumor growth. We argue that Drosophila is a powerful model organism for studying these interactions, and these studies have the potential for improving our understanding of signaling pathways and candidate factors that mediate this conserved interorgan crosstalk. This article is categorized under: Establishment of Spatial and Temporal Patterns Regulation of Size, Proportion, and Timing Early Embryonic Development Development to the Basic Body Plan Invertebrate Organogenesis Flies
Publisher: Elsevier BV
Date: 03-2022
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.YDBIO.2017.08.011
Abstract: Chordates are characterised by contractile muscle on either side of the body that promotes movement by side-to-side undulation. In the lineage leading to modern jawed vertebrates (crown group gnathostomes), this system was refined: body muscle became segregated into distinct dorsal (epaxial) and ventral (hypaxial) components that are separately innervated by the medial and hypaxial motors column, respectively, via the dorsal and ventral ramus of the spinal nerves. This allows full three-dimensional mobility, which in turn was a key factor in their evolutionary success. How the new gnathostome system is established during embryogenesis and how it may have evolved in the ancestors of modern vertebrates is not known. Vertebrate Engrailed genes have a peculiar expression pattern as they temporarily demarcate a central domain of the developing musculature at the epaxial-hypaxial boundary. Moreover, they are the only genes known with this particular expression pattern. The aim of this study was to investigate whether Engrailed genes control epaxial-hypaxial muscle development and innervation. Investigating chick, mouse and zebrafish as major gnathostome model organisms, we found that the Engrailed expression domain was associated with the establishment of the epaxial-hypaxial boundary of muscle in all three species. Moreover, the outgrowing epaxial and hypaxial nerves orientated themselves with respect to this Engrailed domain. In the chicken, loss and gain of Engrailed function changed epaxial-hypaxial somite patterning. Importantly, in all animals studied, loss and gain of Engrailed function severely disrupted the pathfinding of the spinal motor axons, suggesting that Engrailed plays an evolutionarily conserved role in the separate innervation of vertebrate epaxial-hypaxial muscle.
Publisher: Elsevier BV
Date: 10-2004
Publisher: Wiley
Date: 2006
DOI: 10.1002/DVDY.20832
Abstract: Trunk skeletal muscles are segregated into dorsomedial epaxial and ventrolateral hypaxial muscles, separated by a myoseptum. In amniotes, they are generated from a transient structure, the dermomyotome, which lays down muscle, namely the myotome underneath. However, the dermomyotome and myotome are dorsoventrally continuous, with no morphologically defined epaxial-hypaxial boundary. The transcription factors En1 and Sim1 have been shown to molecularly sub ide the amniote dermomyotome, with En1 labeling the epaxial dermomyotome and Sim1 the hypaxial counterpart. Here, we demonstrate that En1 and Sim1 expression persists in cells leaving the dermomyotome, superimposing the expression boundary onto muscle and skin. En1-expressing cells colonize the myotome initially from the rostral and caudal lips, and slightly later, directly from the de-epithelializing dermomyotomal center. En1 expression in the myotome is concomitant with the appearance of Fgfr4/Pax7-expressing mitotically active myoblasts. This finding suggests that Fgfr4+/Pax7+/En1+ cells carry their expression with them when entering the myotome. Furthermore, it suggests that the epaxial-hypaxial boundary of the myotome is established through the late arising, mitotically active myoblasts.
Publisher: Informa UK Limited
Date: 1989
Publisher: Hindawi Limited
Date: 30-08-2018
DOI: 10.1155/2018/7214974
Publisher: Cold Spring Harbor Laboratory
Date: 13-06-2023
DOI: 10.1101/2023.06.10.544444
Abstract: Cancer cachexia is a wasting disease suffered by advanced stage cancer patients and ultimately causes ∼30% of cancer mortalities. Clinical observations have shown that extracellular matrix (ECM) remodelling which leads to fibrosis in the adipose tissue is a key feature of cancer cachexia. However, the molecular regulators of adipose ECM remodelling are not known and how this leads to muscle wasting is unclear. In this study, using a Drosophila cachexia model, we found that in the adipose tissue of both wildtype and tumour bearing animals, insulin and TGF-β signalling converge via a BMP antagonist short gastrulation ( sog ) to regulate ECM remodelling. In tumour bearing animals, the aberrant ECM accumulation in the fatbody, contributes towards muscle detachment by preventing ECM secretion and subsequently depleting muscles of fatbody-secreted ECM proteins. Strikingly, activation of insulin signalling, inhibition of TGF-β signalling, or modulation of ECM secretion via SPARC or Rab10 in the fatbody, was able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.
Publisher: EMBO
Date: 25-02-2019
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2022
DOI: 10.1101/2022.07.24.501087
Abstract: Dedifferentiation is the reversion of differentiated cells to a stem cell like fate, whereby, the gene expression program of mature cells is altered and genes associated with multipotency are expressed. Appropriate terminal differentiation of NSCs is essential for restricting the overall number of neurons produced in addition, faithful production of neuronal subtypes that populate the brain is important for NSC function. Both characteristics of NSCs are specified through temporal patterning of the NSCs driven by the successive expression of temporal transcription factors (tTFs). In this study, we found that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo timely expression of temporal transcription factors (tTFs), where they express mid-tTF, Sloppy-paired 1 (Slp-1) and fail to express late-tTF Tailless (Tll) consequently generating an excess of Twin of eyeless (Toy) positive neurons at the expense of Reversed polarity (Repo) positive glial cells. In addition to disrupted production of neuronal/glial progeny, Dpn overexpression also resulted in stalled progression through the cell cycle, and a failure to undergo timely terminal differentiation. Mechanistically, DamID studies demonstrated that Dpn directly binds to both Dichaete (D), a Sox-box transcription factor known to repress Slp-1, as well as a number of cell cycle genes. Promoting cell cycle progression or overexpression of D were able to re-trigger the progression of the temporal series in dedifferentiated NBs, restoring both neuronal ersity and timely NB terminal differentiation.
Publisher: EMBO
Date: 06-10-2020
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.CUB.2016.02.009
Abstract: A key question in developmental neurobiology is how neural stem cells regulate their proliferative potential and cellular ersity and thus specify the overall size of the brain. Drosophila melanogaster neural stem cells (neuroblasts) are known to regulate their ability to self-renew by asymmetric cell ision and produce different types of neurons and glia through sequential expression of temporal transcription factors [1]. Here, we show that the conserved Hippo pathway, a key regulator of epithelial organ size [2-4], restricts neuroblast proliferative potential and neuronal cell number to regulate brain size. The inhibition of Hippo pathway activity via depletion of the core kinases Tao-1, Hippo, or Warts regulates several key characteristics of neuroblasts during postembryonic neurogenesis. The Hippo pathway is required to maintain timely entry and exit from neurogenesis by regulating both neuroblast reactivation from quiescence and the time at which neuroblasts undergo terminal differentiation. Further, it restricts neuroblast cell-cycle speed, specifies cell size, and alters the proportion of neuron types generated during postembryonic neurogenesis. Collectively, deregulation of Hippo signaling in neuroblasts causes a substantial increase in overall brain size. We show that these effects are mediated via the key downstream transcription co-activator Yorkie and that, indeed, Yorkie overexpression in neuroblasts is sufficient to cause brain overgrowth. These studies reveal a novel mechanism that controls stem cell proliferative potential during postembryonic neurogenesis to regulate brain size.
Publisher: Elsevier BV
Date: 05-2000
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2019
End Date: 2021
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2019
End Date: 06-2022
Amount: $455,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 12-2022
Amount: $713,125.00
Funder: Australian Research Council
View Funded Activity