The Experts below are selected from a list of 3945 Experts worldwide ranked by ideXlab platform
David J Anderson - One of the best experts on this subject based on the ideXlab platform.
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Prokineticin 2 is a target gene of proneural basic helix-loop-helix factors for olfactory bulb neurogenesis
The Journal of biological chemistry, 2007Co-Authors: Chengkang Zhang, David J Anderson, Yi E. Sun, Qun-yong ZhouAbstract:Prokineticin 2, a cysteine-rich secreted protein, regulates diverse biological functions including the neurogenesis of olfactory bulb. Here we show that the PK2 gene is a functional target gene of proneural basic helix-loop-helix (bHLH) factors. Neurogenin 1 and MASH1 activate PK2 transcription by binding to E-box motifs on the PK2 promoter with the same set of E-boxes critical for another pair of bHLH factors, CLOCK and BMAL1, in the regulation of circadian clock. Our results establish PK2 as a common functional target gene for different bHLH transcriptional factors in mediating their respective functions.
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the bhlh transcription factor olig2 promotes oligodendrocyte differentiation in collaboration with nkx2 2
Neuron, 2001Co-Authors: Qiao Zhou, Gloria Choi, David J AndersonAbstract:Olig2, a basic helix-loop-helix (bHLH) transcription factor, is expressed in a restricted domain of the spinal cord ventricular zone that sequentially generates motoneurons and oligodendrocytes. Just prior to oligo-dendrocyte precursor formation, the domains of Olig2 and Nkx2.2 expression switch from being mutually exclusive to overlapping, and Neurogenins1 and 2 are extinguished within this region. Coexpression of Olig2 with Nkx2.2 in the spinal cord promotes ectopic and precocious oligodendrocyte differentiation. Both proteins function as transcriptional repressors in this assay. This effect is blocked by forced expression of Neurogenin1. By contrast, misexpression of Olig2 alone derepresses Neurogenins and promotes motoneuron differentiation. Olig2 therefore functions sequentially in motoneuron and oligodendrocyte fate specification. This dual action is enabled by spatio-temporal changes in the expression domains of other transcription factors with which Olig2 functionally interacts.
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The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2." Neuron 31
2001Co-Authors: Qiao Zhou, David J Anderson, Gloria Choi, Division Of BiologyAbstract:Olig2, a basic helix-loop-helix (bHLH) transcription factor, is expressed in a restricted domain of the spinal cord ventricular zone that sequentially generates mo-toneurons and oligodendrocytes. Just prior to oligodendrocyte precursor formation, the domains of Olig2 and Nkx2.2 expression switch from being mutually ex-clusive to overlapping, and Neurogenins1 and 2 are extinguished within this region. Coexpression of Olig2 with Nkx2.2 in the spinal cord promotes ectopic and precocious oligodendrocyte differentiation. Both proteins function as transcriptional repressors in this assay. This effect is blocked by forced expression of Neurogenin1. By contrast, misexpression of Olig2 alone derepresses Neurogenins and promotes motoneuron differentiation. Olig2 therefore functions sequentially in motoneuron and oligodendrocyte fate specification. This dual action is enabled by spatio-temporal changes in the expression domains of other transcription factors with which Olig2 functionally in-teracts
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Hes6 acts in a positive feedback loop with the Neurogenins to promote neuronal differentiation.
Development (Cambridge England), 2000Co-Authors: Naoko Koyano-nakagawa, David J Anderson, Jaesang Kim, Chris KintnerAbstract:During the development of the vertebrate nervous system, neurogenesis is promoted by proneural bHLH proteins such as the Neurogenins, which act as potent transcriptional activators of neuronal differentiation genes. The pattern by which these proteins promote neuronal differentiation is thought to be governed by inhibitors, including a class of transcriptional repressors called the WRPW-bHLH proteins, which are similar to Drosophila proteins encoded by hairy and genes in the enhancer of split complex (E-(SPL)-C). Here, we describe the isolation and characterization of Hes6, which encodes a novel WRPW-bHLH protein expressed during neurogenesis in mouse and Xenopus embryos. We show that Hes6 expression follows that of Neurogenins but precedes that of the neuronal differentiation genes. We provide several lines of evidence to show that Hes6 expression occurs in developing neurons and is induced by the proneural bHLH proteins but not by the Notch pathway. When ectopically expressed in Xenopus embryos, Hes6 promotes neurogenesis. The properties of Hes6 distinguish it from other members of the WRPW-bHLH family in vertebrates, and suggest that it acts in a positive-feedback loop with the proneural bHLH proteins to promote neuronal differentiation.
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Lineages and transcription factors in the specification of vertebrate primary sensory neurons.
Current opinion in neurobiology, 1999Co-Authors: David J AndersonAbstract:Recent advances have indentified some of the key transcriptional regulators of mammalian genes, the Neurogenins. Neurogenins 1 and 2 appear to control distinct sublineages for different classes of sensory neurons, including a ‘pioneer’ lineage for proprioceptors specified early in neural crest migration. Neurogenins act via a cascade of downstream transcriptional regulators, some of which have been identified.
Anna Philpott - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation in intrinsically disordered regions regulates the activity of Neurogenin2.
BMC Biochemistry, 2014Co-Authors: Gary S Mcdowell, Christopher J Hindley, Guy Lippens, Isabelle Landrieu, Anna PhilpottAbstract:BackgroundNeuronal differentiation is largely under the control of basic Helix-Loop-Helix (bHLH) proneural transcription factors that play key roles during development of the embryonic nervous system. In addition to well-characterised regulation of their expression, increasing evidence is emerging for additional post-translational regulation of proneural protein activity. Of particular interest is the bHLH proneural factor Neurogenin2 (Ngn2), which orchestrates progression from neural progenitor to differentiated neuron in several regions of the central nervous system. Previous studies have demonstrated a key role for cell cycle-dependent multi-site phosphorylation of Ngn2 protein at Serine-Proline (SP) sites for regulation of its neuronal differentiation activity, although the potential structural and functional consequences of phosphorylation at different regions of the protein are unclear.ResultsHere we characterise the role of phosphorylation of specific regions of Ngn2 on the stability of Ngn2 protein and on its neuronal differentiation activity in vivo in the developing embryo, demonstrating clearly that the location of SP sites is less important than the number of SP sites available for control of Ngn2 activity in vivo. We also provide structural evidence that Ngn2 contains large, intrinsically disordered regions that undergo phosphorylation by cyclin-dependent kinases (cdks).ConclusionsPhosphorylation of Ngn2 occurs in both the N- and C-terminal regions, either side of the conserved basic Helix-Loop-Helix domain. While these phosphorylation events do not change the intrinsic stability of Ngn2, phosphorylation on multiple sites acts to limit its ability to drive neuronal differentiation in vivo. Phosphorylated regions of Ngn2 are predicted to be intrinsically disordered and cdk-dependent phosphorylation of these intrinsically disordered regions contributes to Ngn2 regulation.
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Hes6 Is Required for the Neurogenic Activity of Neurogenin and NeuroD
PloS one, 2011Co-Authors: Kasumi Murai, Anna Philpott, Philip H. JonesAbstract:In the embryonic neural plate, a subset of precursor cells with neurogenic potential differentiates into neurons. This process of primary neurogenesis requires both the specification of cells for neural differentiation, regulated by Notch signaling, and the activity of neurogenic transcription factors such as neurogenin and NeuroD which drive the program of neural gene expression. Here we study the role of Hes6, a member of the hairy enhancer of split family of transcription factors, in primary neurogenesis in Xenopus embryos. Hes6 is an atypical Hes gene in that it is not regulated by Notch signaling and promotes neural differentiation in mouse cell culture models. We show that depletion of Xenopus Hes6 (Xhes6) by morpholino antisense oligonucleotides results in a failure of neural differentiation, a phenotype rescued by both wild type Xhes6 and a Xhes6 mutant unable to bind DNA. However, an Xhes6 mutant that lacks the ability to bind Groucho/TLE transcriptional co-regulators is only partly able to rescue the phenotype. Further analysis reveals that Xhes6 is essential for the induction of neurons by both neurogenin and NeuroD, acting via at least two distinct mechanisms, the inhibition of antineurogenic Xhairy proteins and by interaction with Groucho/TLE family proteins. We conclude Xhes6 is essential for neurogenesis in vivo, acting via multiple mechanisms to relieve inhibition of proneural transcription factor activity within the neural plate.
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Regulation of neurogenin stability by ubiquitin-mediated proteolysis
The Biochemical journal, 2007Co-Authors: Jonathan M.d. Vosper, Christelle S. Fiore-heriche, Ian Horan, Katherine Wilson, Helen M. Wise, Anna PhilpottAbstract:NGN (neurogenin), a proneural bHLH (basic helix-loop-helix) transcription factor, plays a central role in promoting neuronal specification and differentiation in many regions of the central nervous system. NGN activity has been shown extensively to be controlled at the transcriptional level. However, in addition, recent findings have indicated that the levels of NGN protein may also be regulated. In the present study, we have demonstrated that NGN protein stability was regulated in both Xenopus embryos and P19 embryonal carcinoma cells, a mammalian neuronal model system. In both systems, NGN was a highly unstable protein that was polyubiquitinated for destruction by the proteasome. NGN binds to DNA in complex with its heterodimeric E-protein partners E12 or E47. We observed that NGN was stabilized by the presence of E12/E47. Moreover, NGN was phosphorylated, and mutation of a single threonine residue substantially reduced E12-mediated stabilization of NGN. Thus E-protein partner binding and phosphorylation events act together to stabilize NGN, promoting its accumulation when it can be active.
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Regulation of neurogenin stability by ubiquitin-mediated proteolysis
Biochemical Journal, 2007Co-Authors: Jonathan M.d. Vosper, Christelle S. Fiore-heriche, Ian Horan, Kate Wilson, Helen Wise, Anna PhilpottAbstract:Neurogenin (NGN), a proneural basic helix loop helix transcription factor, plays a central role in promoting neuronal specification and differentiation in many regions of the central nervous system. NGN activity has been shown extensively to be controlled at the transcriptional level. However, in addition, recent experiments have indicated that the levels of NGN protein may also be regulated. Here, we demonstrate that NGN protein stability is regulated in both Xenopus embryos and P19 embryonal carcinoma cells, a mammalian neuronal model system. In both systems, NGN is a highly unstable protein that is poly-ubiquitinated for destruction by the proteasome. NGN binds to DNA in complex with its heterodimeric E protein partners E12 or E47. We see that NGN is stabilised by the presence of E12/E47. Moreover, NGN is phosphorylated, and mutation of a single threonine residue substantially reduces E12-mediated stabilisation of NGN. Thus, E-protein partner binding and phosphorylation events act together to stabilise NGN, promoting its accumulation when it can be active.
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p27Kip1 independently promotes neuronal differentiation and migration in the cerebral cortex
Bulletin et memoires de l'Academie royale de medecine de Belgique, 2007Co-Authors: Laurent Nguyen, Carol Schuurmans, Carlos Parras, Anna Philpott, Arnaud Besson, J Ik-tsen Heng, Lydia Teboul, James M. RobertsAbstract:The generation of glutamatergic neurons by stem and progenitor cells is a complex process involving 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 program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27Kip1 plays an important role in neurogenesis in the mouse cerebral cortex, by promoting the differentiation and radial migration of cortical projection neurons. Importantly, p27Kip1 promotes neuronal differentiation and neuronal migration via two distinct mechanisms, which are themselves independent of the cell cycle regulatory function of p27Kip1. p27Kip1 inactivation by gene targeting or RNA interference results in neuronal differentiation and radial migration defects, demonstrating that p27Kip1 regulates cell migration in vivo. The differentiation defect, but not the migration defect, is rescued by overexpression of the proneural gene Neurogenin 2. p27Kip1 acts by stabilizing Neurogenin 2 protein, an activity carried by the N-terminal half of the protein. The migration defect resulting from p27Kp1 inactivation is rescued by blocking RhoA signalling, an activity that resides in the c-terminal half of p27Kip1. Thus, p27Kip1 plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.
Bassem A Hassan - One of the best experts on this subject based on the ideXlab platform.
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Beyond proneural: emerging functions and regulations of proneural proteins
Current Opinion in Neurobiology, 2017Co-Authors: François Guillemot, Bassem A HassanAbstract:Proneural proteins, which include Ascl1, Atoh1 and Neurogenins e ´ piniè re in vertebrates and Achaete-Scute proteins and Atonal in Drosophila, are expressed in the developing nervous system throughout the animal kingdom and have an essential and well-characterised role in specifying the neural identity of progenitors. New properties and additional roles of these factors have emerged in recent years, including the regulation of stem cell proliferation and the capacity to reprogram many types of cells into neurons. This review will focus on these recent findings. The review will also discuss the mechanisms that allow proneural proteins to induce the transcription of their target genes in different chromatin contexts and the phosphorylation events and other post-transcriptional mechanisms that regulate the proneural proteins themselves.
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The Drosophila neurogenin Tap functionally interacts with the Wnt-PCP pathway to regulate neuronal extension and guidance
Development (Cambridge England), 2016Co-Authors: Liqun Yuan, Zeynep Okray, Natalie De Geest, Annelies Claeys, Eric Bellefroid, Bassem A Hassan, Xi Ren, Jiekun Yan, Xiaojiang QuanAbstract:The neurogenin (Ngn) transcription factors control early neurogenesis and neurite outgrowth in mammalian cortex. In contrast to their proneural activity, their function in neurite growth is poorly understood. Drosophila has a single predicted Ngn homolog, Tap, of unknown function. Here we show that Tap is not a proneural protein in Drosophila but is required for proper axonal growth and guidance of neurons of the mushroom body, a neuropile required for associative learning and memory. Genetic and expression analyses suggest that Tap inhibits excessive axonal growth by fine regulation of the levels of the Wnt signaling adaptor protein Dishevelled.
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the drosophila neurogenin tap controls axonal growth through the wnt adaptor protein dishevelled
bioRxiv, 2015Co-Authors: Liqun Yuan, Shu Hu, Zeynep Okray, Natalie De Geest, Annelies Claeys, Eric Bellefroid, Bassem A Hassan, Xiaojiang QuanAbstract:The Neurogenin (Ngn) transcription factors control early neurogenesis and neurite outgrowth in mammalian cortex. In contrast to their proneural activity, their function in neurite growth is poorly understood. Drosophila has a single predicted Ngn homologue called Tap, whose function is completely unknown. Here we show that Tap is not a proneural protein in Drosophila but is required for proper axonal growth and guidance of neurons of the mushroom body (MB), a neuropile required for associative learning and memory. Genetic and expression analyses suggest that Tap inhibits excessive axonal growth by fine regulation of the levels of the Wnt signaling adaptor protein, Dishevelled.
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Neurogenins in brain development and disease: An overview
Archives of biochemistry and biophysics, 2014Co-Authors: Liqun Yuan, Bassem A HassanAbstract:The production of neurons, astrocytes and oligodendrocytes is regulated by a group of transcription factors, which determine cell fates and specify subtype identities in the nervous system. Here we focus on profiling the distinct roles of Neurogenin (Ngn or Neurog) family members during the neuronal development. Ngn proteins are tightly regulated to be expressed at defined times and positions of different progenitor cell pools. In addition to their well-elucidated proneural function, Ngn proteins play various critical roles to specify or maintain cell fate and regulate neurite outgrowth and targeting in the central nervous system. Finally, Ngns have been associated with neuronal disorders. Therefore understanding the function and regulation of Ngns will not only improve the understanding of the molecular mechanism underlying the development of nervous system, but may also provide insight into neuronal disease.
Gerard Gradwohl - One of the best experts on this subject based on the ideXlab platform.
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Genetic determinants of pancreatic epsilon-cell development.
Developmental Biology, 2005Co-Authors: R Scott Heller, Gerard Gradwohl, Marjorie Jenny, Patrick Collombat, Ahmed Mansouri, Catherine Tomasetto, Ole D Madsen, Georg Mellitzer, Palle SerupAbstract:Recently, the expression of the peptide hormone ghrelin was detected in alpha-cells of the islets of Langerhans as well as in epsilon-cells, a newly discovered endocrine cell type, but it remains unclear how the latter is related in lineage to the four classical islet cell types, alpha-, beta-, delta-, and PP-cells. Here, we provide further evidence that ghrelin is predominantly produced in the alpha-cells of mouse islets but also in single hormone ghrelin-secreting epsilon-cells. We additionally demonstrate that pancreatic epsilon-cells derive from Neurogenin3-expressing precursor cells and their genesis depends on Neurogenin3 activity. Furthermore, our data indicate that the number of ghrelin-producing cells is differentially regulated during pancreas morphogenesis by the homeodomain-containing transcription factors Arx, Pax4, and Pax6. Arx mutants lack ghrelin+ glucagon+ alpha-cells whereas Pax4 mutants develop an excess of these cells. Importantly, the ghrelin+ glucagon- epsilon-cell population is not affected following Arx or Pax4 disruption. In contrast, the loss of Pax6 provokes an unexpected increase of the ghrelin+ glucagon- epsilon-cell number which is not due to increased proliferation. Thus, we demonstrate that the development of ghrelin-producing cells is differentially dependent on Neurogenin3 in different domains of the gastrointestinal tract and that, in the endocrine pancreas, epsilon-cell genesis does not require Arx or Pax4 activities but is antagonized by Pax6.
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Neurogenesis in hippocampal slice cultures.
Molecular and Cellular Neuroscience, 2004Co-Authors: Olivier Raineteau, Gerard Gradwohl, Lotty Rietschin, Beat H. GähwilerAbstract:A major challenge in studying neurogenesis in the adult brain is gaining access to neural stem cells for experimental manipulation. We developed an approach utilizing mouse hippocampal organotypic cultures to characterize neurogenesis under controlled conditions. After 2 weeks in culture, double immunostaining using the mitotic marker BrdU and cell type-specific markers revealed persistent proliferation of various cell types. The birth of new neurons was restricted to a third subgranular germinal zone as shown by analysis of the expression pattern of the proneural transcription factor neurogenin-2 and colocalization of BrdU with neuronal phenotypic markers. The regional distribution of newly born neurons closely resembled that observed in vivo in the adult hippocampus. Furthermore, neurogenesis was increased by chronic application of epidermal growth factor (EGF) and abolished by adding serum to the culture medium. Our study therefore establishes the hippocampal slice culture as a promising ex vivo model for investigating neurogenesis.
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the bhlh protein neurogenin 2 is a determination factor for epibranchial placode derived sensory neurons
Neuron, 1998Co-Authors: Carol Fode, Gerard Gradwohl, Xavier Morin, Andree Dierich, Marianne Lemeur, Christo GoridisAbstract:Abstract neurogenin2 encodes a neural-specific basic helix–loop–helix (bHLH) transcription factor related to the Drosophila proneural factor atonal. We show here that the murine ngn2 gene is essential for development of the epibranchial placode–derived cranial sensory ganglia. An ngn2 null mutation blocks the delamination of neuronal precursors from the placodes, the first morphological sign of differentiation in these lineages. Mutant placodal cells fail to express downstream bHLH differentiation factors and the Notch ligand Delta-like 1. These data suggest that ngn2 functions like the Drosophila proneural genes in the determination of neuronal fate in distal cranial ganglia. Interestingly, the homeobox gene Phox2a is activated independently of ngn2 in epibranchial placodes, suggesting that neuronal fate and neuronal subtype identity may be specified independently in cranial sensory ganglia.
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The bHLH Protein NEUROGENIN 2 Is a Determination Factor for Epibranchial Placode–Derived Sensory Neurons
Neuron, 1998Co-Authors: Carol Fode, Gerard Gradwohl, Xavier Morin, Andree Dierich, Marianne Lemeur, Christo GoridisAbstract:Abstract neurogenin2 encodes a neural-specific basic helix–loop–helix (bHLH) transcription factor related to the Drosophila proneural factor atonal. We show here that the murine ngn2 gene is essential for development of the epibranchial placode–derived cranial sensory ganglia. An ngn2 null mutation blocks the delamination of neuronal precursors from the placodes, the first morphological sign of differentiation in these lineages. Mutant placodal cells fail to express downstream bHLH differentiation factors and the Notch ligand Delta-like 1. These data suggest that ngn2 functions like the Drosophila proneural genes in the determination of neuronal fate in distal cranial ganglia. Interestingly, the homeobox gene Phox2a is activated independently of ngn2 in epibranchial placodes, suggesting that neuronal fate and neuronal subtype identity may be specified independently in cranial sensory ganglia.
Jacqueline E. Lee - One of the best experts on this subject based on the ideXlab platform.
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Basic helix-loop-helix genes in neural development.
Current opinion in neurobiology, 1997Co-Authors: Jacqueline E. LeeAbstract:Several major advances in the understanding of the regulation of vertebrate neurogenesis by members of the basic helix-loop-helix (bHLH) protein family have been made in the past year. Specifically, a number of bHLH genes have been cloned and shown to convert non-neuronal fate to neuronal fate when expressed ectopically. In particular, studies on NeuroD and Neurogenin suggest a regulatory pathway, providing powerful molecular tools to study vertebrate neurogenesis.