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Helen M. Cooper - One of the best experts on this subject based on the ideXlab platform.
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Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus
Elsevier, 2017Co-Authors: Conor J. O’leary, Cathrin C. Nourse, Natalie K. Lee, Amanda White, Michael Langford, Kai Sempert, Stacey J. Cole, Helen M. CooperAbstract:Denudation of the ependyma due to loss of cell adhesion mediated by cadherin-based adherens junctions is a common feature of perinatal hydrocephalus. Junctional stability depends on the interaction between cadherins and the actin cytoskeleton. However, the molecular mechanism responsible for recruiting the actin nucleation machinery to the ependymal junction is unknown. Here, we reveal that loss of the netrin/RGM receptor, Neogenin, leads to severe hydrocephalus. We show that Neogenin plays a critical role in actin nucleation in the ependyma by anchoring the WAVE regulatory complex (WRC) and Arp2/3 to the cadherin complex. Blocking Neogenin binding to the Cyfip1/Abi WRC subunit results in actin depolymerization, junctional collapse, and denudation of the postnatal ventricular zone. In the embryonic cortex, this leads to loss of radial progenitor adhesion, aberrant neuronal migration, and neuronal heterotopias. Therefore, Neogenin-WRC interactions play a fundamental role in ensuring the fidelity of the embryonic ventricular zone and maturing ependyma
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Neogenin recruitment of the wave regulatory complex maintains adherens junction stability and tension
Nature Communications, 2016Co-Authors: Natalie K. Lee, Nicole H. Wilson, Amanda White, Ka Wai Fok, Conor J Oleary, Hayley L Cox, Magdalene Michael, Alpha S Yap, Helen M. CooperAbstract:To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the actin nucleation machinery governing junctional stability. Loss of Neogenin perturbs AJs and attenuates junctional tension. Neogenin promotes actin nucleation at AJs by recruiting the Wave regulatory complex (WRC) and Arp2/3. A direct interaction between the Neogenin WIRS domain and the WRC is crucial for the spatially restricted recruitment of the WRC to the junction. Thus, we provide the first example of a functional WIRS-WRC interaction in epithelia. We further show that Neogenin regulates cadherin recycling at the AJ. In summary, we identify Neogenin as a pivotal component of the AJ, where it influences both cadherin dynamics and junctional tension.
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the netrin rgm receptor Neogenin controls adult neurogenesis by promoting neuroblast migration and cell cycle exit
Stem Cells, 2015Co-Authors: Conor J Oleary, Amanda White, Danakai Bradford, Min Chen, Daniel G Blackmore, Helen M. CooperAbstract:A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo(gt/gt)) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo(gt/gt) olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neo(gt/gt) RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS.
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characterization of the netrin rgma receptor Neogenin in neurogenic regions of the mouse and human adult forebrain
The Journal of Comparative Neurology, 2010Co-Authors: Danakai Bradford, Richard L M Faull, Maurice A Curtis, Helen M. CooperAbstract:In the adult rodent forebrain, astrocyte-like neural stem cells reside within the subventricular zone (SVZ) and give rise to progenitors and neuroblasts, which then undergo chain migration along the rostral migratory stream (RMS) to the olfactory bulb, where they mature into fully functional interneurons. Neurogenesis also occurs in the adult human SVZ, where neural precursors similar to the rodent astrocyte-like stem cell and neuroblast have been identified. A migratory pathway equivalent to the rodent RMS has also recently been described for the human forebrain. In the embryo, the guidance receptor Neogenin and its ligands netrin-1 and RGMa regulate important neurogenic processes, including differentiation and migration. We show in this study that Neogenin is expressed on neural stem cells (B cells), progenitor cells (C cells), and neuroblasts (A cells) in the adult mouse SVZ and RMS. We also show that netrin-1 and RGMa are ideally placed within the neurogenic niche to activate Neogenin function. Moreover, we find that Neogenin and RGMa are also present in the neurogenic regions of the human adult forebrain. We show that Neogenin is localized to cells displaying stem cell (B cell)-like characteristics within the adult human SVZ and RMS and that RGMa is expressed by the same or a closely apposed cell population. This study supports the hypothesis that, as in the embryo, Neogenin regulates fundamental signalling pathways important for neurogenesis in the adult mouse and human forebrain.
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Neogenin and rgma control neural tube closure and neuroepithelial morphology by regulating cell polarity
The Journal of Neuroscience, 2008Co-Authors: Nigel Kee, Nicole H. Wilson, Brian Key, Melissa De Vries, Danakai Bradford, Helen M. CooperAbstract:In humans, neural tube closure defects occur in 1:1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel signaling pathway essential for radial intercalation and epithelialization during neural fold elevation and neural tube morphogenesis.
Toshihide Yamashita - One of the best experts on this subject based on the ideXlab platform.
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Repulsive Guidance Molecule A Regulates Adult Neurogenesis Via the Neogenin Receptor.
Neuroscience insights, 2020Co-Authors: Toke Jost Isaksen, Toshihide YamashitaAbstract:Repulsive guidance molecule A (RGMa) exhibits repulsive guidance of axonal growth and regulates neuronal differentiation during development of the mammalian brain. In this commentary, we describe the findings of our recent paper, "Repulsive Guidance Molecule A Suppresses Adult Neurogenesis," and discuss a possible model for RGMa suppression of newborn neurons that fail to properly migrate into the granular cell layer. In the study, we provided evidence that RGMa suppressed neurite growth and survival of newborn neurons in the adult dentate gyrus. This effect depends on the multifunctional Neogenin receptor expressed in adult neural stem cells through activation of the Rho-associated protein kinase leading to neurite growth inhibition and ultimately cell death. It should be noted that both RGMa and Neogenin interact with several well-described molecules, including bone morphogenetic proteins, that regulate neuronal development. Thus, it is likely that RGMa interacts with other intricate molecular networks that regulate adult neurogenesis.
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The roles of RGMa-Neogenin signaling in inflammation and angiogenesis
Inflammation and Regeneration, 2017Co-Authors: Yuki Fujita, Toshihide YamashitaAbstract:Repulsive guidance molecule (RGM) is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that has diverse functions in the developing and pathological central nervous system (CNS). The binding of RGM to its receptor Neogenin regulates axon guidance, neuronal differentiation, and survival during the development of the CNS. In the pathological state, RGM expression is induced after spinal cord injury, and the inhibition of RGM promotes axon growth and functional recovery. Furthermore, RGM expression is also observed in immune cells, and RGM regulates inflammation and neurodegeneration in autoimmune encephalomyelitis. RGMa induces T cell activation in experimental autoimmune encephalomyelitis (EAE), which is the animal model of multiple sclerosis (MS). RGM is expressed in pathogenic Th17 cells and induces neurodegeneration by binding to Neogenin. Angiogenesis is an additional key factor involved in the pathophysiology of EAE. Via Neogenin, treatment with RGMa can suppress endothelial tube formation; this finding indicates that RGMa inhibits neovascularization. These observations suggest the feasibility of utilizing the RGMa-Neogenin signaling pathway as a therapeutic target to overcome inflammation and neurodegeneration. This review focuses on the molecular mechanisms of inflammation and angiogenesis via RGM-Neogenin signaling.
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Identification of the Neogenin-binding site on the repulsive guidance molecule A.
PloS one, 2012Co-Authors: Takahide Itokazu, Yuki Fujita, Ryosuke Takahashi, Toshihide YamashitaAbstract:Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the chick retinotectal system. RGMa, one of the 3 isoforms found in mammals, is involved in laminar patterning, cephalic neural tube closure, axon guidance, and inhibition of axonal regeneration. In addition to its roles in the nervous system, RGMa plays a role in enhancing helper T-cell activation. Binding of RGM to its receptor, Neogenin, is considered necessary to transduce these signals; however, information on the binding of RGM to Neogenin is limited. Using co-immunoprecipitation studies, we have identified that the RGMa region required for binding to Neogenin contains amino acids (aa) 259–295. Synthesized peptide consisting of aa 284–293 directly binds to the extracellular domain (ECD) of recombinant Neogenin, and addition of this peptide inhibits RGMa-induced growth cone collapse in mouse cortical neurons. Thus, we propose that this peptide is a promising lead in finding reagents capable of inhibiting RGMa signaling.
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TACE cleaves Neogenin to desensitize cortical neurons to the repulsive guidance molecule
Neuroscience research, 2011Co-Authors: Yusuke Okamura, Eiji Kohmura, Toshihide YamashitaAbstract:Neogenin is a receptor for netrins and proteins of the repulsive guidance molecule (RGM) family. It regulates several key developmental processes within the nervous system. The binding of RGMa to Neogenin induces the inhibition of neurite outgrowth and the collapse of the growth cone of neurons. Here, we report that a disintegrin and metalloprotease (ADAM) transmembrane protein regulates the sensitivity of neurons to RGMa, by inducing the shedding of the ectodomain of Neogenin. The extracellular domain of Neogenin is directly associated with and cleaved off by the tumor necrosis factor-α converting enzyme (TACE), also called ADAM17. TACE is endogenously expressed in embryonic cortical neurons and regulates the cleavage of Neogenin, and the inhibition of TACE in turn enhances RGMa-induced inhibition of neurite outgrowth and collapse of the growth cone. Conversely, exogenous expression of TACE abolishes the effect of RGMa. Therefore, TACE may play a role in modulating the RGM-induced repulsive behavior of neurons by regulating the expression of Neogenin on the cell surface.
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Neogenin, a receptor for bone morphogenetic proteins
Journal of Biological Chemistry, 2011Co-Authors: Meiko Hagihara, Chikahisa Higuchi, Mitsuharu Endo, Katsuhiko Hata, Hideki Yoshikawa, Kunio Takaoka, Toshihide YamashitaAbstract:Bone morphogenetic proteins (BMPs) regulate many mammalian physiologic and pathophysiologic processes. These proteins bind with the kinase receptors BMPR-I and BMPR-II, thereby activating Smad transcription factor. In this study, we demonstrate that Neogenin, a receptor for netrins and proteins of the repulsive guidance molecule family, is a receptor for BMPs and modulates Smad signal transduction. Neogenin was found to bind directly with BMP-2, BMP-4, BMP-6, and BMP-7. Knockdown of Neogenin in C2C12 cells resulted in the enhancement of the BMP-2-induced processes of osteoblastic differentiation and phosphorylation of Smad1, Smad5, and Smad8. Conversely, overexpression of Neogenin in C2C12 cells suppressed these processes. Our results also indicated that BMP-induced activation of RhoA was mediated by Neogenin. Inhibition of RhoA promoted BMP-2-induced processes of osteoblastic differentiation and phosphorylation of Smad1/5/8. However, treatment with Y-27632, an inhibitor of Rho-associated protein kinase, did not modulate BMP-induced phosphorylation of Smad1/5/8. Taken together, our findings suggest that Neogenin negatively regulates the functions of BMP and that this effect of Neogenin is mediated by the activation of RhoA.
Wen Cheng Xiong - One of the best experts on this subject based on the ideXlab platform.
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Neogenin loss in neural crest cells results in persistent hyperplastic primary vitreous formation
Journal of Molecular Cell Biology, 2020Co-Authors: Sen Lin, Lin Mei, Wen Cheng Xiong, Dong Sun, Wei Liu, Chunlin ChenAbstract:Neogenin is a transmembrane receptor critical for multiple cellular processes, including neurogenesis, astrogliogenesis, endochondral bone formation, and iron homeostasis. Here we present evidence that loss of Neogenin contributes to pathogenesis of persistent hyperplastic primary vitreous (PHPV) formation, a genetic disorder accounting for ~ 5% of blindness in the USA. Selective loss of Neogenin in neural crest cells (as observed in Wnt1-Cre; Neof/f mice), but not neural stem cells (as observed in GFAP-Cre and Nestin-Cre; Neof/f mice), resulted in a dysregulation of neural crest cell migration or delamination, exhibiting features of PHPV-like pathology (e.g. elevated retrolental mass), unclosed retinal fissure, and microphthalmia. These results demonstrate an unrecognized function of Neogenin in preventing PHPV pathogenesis, implicating Neogenin regulation of neural crest cell delamination/migration and retinal fissure formation as potential underlying mechanisms of PHPV.
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Neogenin a regulator of adult hippocampal neurogenesis prevents depressive like behavior
Cell Death and Disease, 2018Co-Authors: Dong Sun, Lin Mei, Daehoon Lee, Xiang Dong Sun, Lu Zhao, Fu Lei Tang, Jinxiu Pan, Xiao Juan Zhu, Wen Cheng XiongAbstract:Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for Neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of Neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for Neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into Neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in Neogenin-depleted new-born DG neurons; and mice with depletion of Neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of Neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest Neogenin regulation of Gli1 signaling as a possible underlying mechanism.
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Neogenin yap signaling in neocortical astrocytic differentiation
Neurogenesis (Austin Tex.), 2016Co-Authors: Zhihui Huang, Wen Cheng XiongAbstract:Astrocytes, a major type of glial cells in the mammalian central nervous system (CNS), have a wide variety of physiological functions, including formation of the blood brain barrier, and modulation of synaptic transmission and information processing, and maintenance of CNS homeostasis. The signaling pathway initiated by bone morphogenetic protein (BMP) is critical for astrogliogenesis. However, exactly how this pathway regulates astrogliogenesis remains poorly understood. We have recently provided in vitro and in vivo evidence for Neogenin's function in neural stem cells (NSCs) to promote neocortical astrogliogenesis. Neogenin in NSCs as well as astrocytes is required for BMP2 activation of RhoA that promotes YAP (yes-associated protein) nuclear translocation, consequently, YAP interaction with nuclear p-Smad1/5/8, and stabilization of Smad1/5/8 signaling. We have also provided evidence that YAP in NSCs is necessary for neocortical astrogliogenesis, and expression of YAP in Neogenin deficient NSCs diminishes the astrogliogenesis deficit. These recent findings identify an unrecognized function of Neogenin in promoting neocortical astrogliogenesis, and reveal a pathway of BMP2-Neogenin-YAP-Smad1 underlying astrogliogenesis in developing mouse neocortex.
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Neogenin promotes bmp2 activation of yap and smad1 and enhances astrocytic differentiation in developing mouse neocortex
The Journal of Neuroscience, 2016Co-Authors: Zhihui Huang, Lin Mei, Daehoon Lee, Dong Sun, Fu Lei Tang, Xiao Juan Zhu, Ying Wang, Jiliang Zhou, Wen Cheng XiongAbstract:Neogenin, a DCC (deleted in colorectal cancer) family receptor, is highly expressed in neural stem cells (NSCs). However, its function in NSCs remains to be explored. Here we provide in vitro and in vivo evidence for Neogenin9s function in NSCs to promote neocortical astrogliogenesis, but not self-renewal or neural differentiation. Mechanistically, Neogenin in neocortical NSCs was required for BMP2 activation of YAP (yes associated protein). The active/nuclear YAP stabilized phospho-Smad1/5/8 and was necessary for BMP2 induction of astrocytic differentiation. Deletion of yap in mouse neocortical NSCs caused a similar deficit in neocortical astrogliogenesis as that in Neogenin mutant mice. Expression of YAP in Neogenin mutant NSCs diminished the astrocytic differentiation deficit in response to BMP2. Together, these results reveal an unrecognized function of Neogenin in increasing neocortical astrogliogenesis, and identify a pathway of BMP2-Neogenin-YAP-Smad1 for astrocytic differentiation in developing mouse neocortex. SIGNIFICANCE STATEMENT Astrocytes, a major type of glial cells in the brain, play important roles in modulating synaptic transmission and information processing, and maintaining CNS homeostasis. The abnormal astrocytic differentiation during development contributes to dysfunctions of synaptic plasticity and neuropsychological disorders. Here we provide evidence for Neogenin9s function in regulation of the neocortical astrocyte differentiation during mouse brain development. We also provide evidence for the necessity of Neogenin in BMP2/Smad1-induced astrocyte differentiation through YAP. Thus, our findings identify an unrecognized function of Neogenin in mouse neocortical astrocyte differentiation, and suggest a signaling pathway, BMP2-Neogenin-YAP-Smad1, underlying astrogliogenesis in developing mouse neocortex.
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Neogenin as a Receptor for Early Cell Fate Determination in Preimplantation Mouse Embryos
2014Co-Authors: Jae Ho Lee, Wen Cheng Xiong, Churl K Min, Sung Sook Choi, Hae Won Kim, Sang Jin LeeAbstract:The first cell lineage determination in embryos takes place when two cell populations are set apart, each differentiating into the trophectoderm (TE) and inner cell mass (ICM), respectively. It is widely believed that position/polarity cues play a key role in triggering this differentiation, but it remains unclear how extracellular cues are transduced into cell fate determination. Here, we provide evidence that supports that Neogenin is implicated in relaying extracellular cues into the first cell fate determination in preimplantation mouse embryos. A polarized and transient distribution of Neogenin was manifested in early blastomeres. Neogenin up-regulation by its overexpression accelerated ICM development in the blastocyst concomitant with the activation of the ICM-specific transcription factors Oct3/4, Sox2, and Nanog while its depletion by small hairpin RNAs (shRNAs) caused a developmental abnormality of poorly endowed ICM accompanied by the deactivation of Oct3/4, Sox2, and Nanog. Treatment with netrin-1 among Neogenin ligands further impaired both embryonic development and ICM formation while repulsive guidance molecule c (RGMc) led to opposite consequences, enhancing ICM formation. From this study, we propose a model whereby Neogenin interprets its own expression level t
Nicole H. Wilson - One of the best experts on this subject based on the ideXlab platform.
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Neogenin recruitment of the wave regulatory complex maintains adherens junction stability and tension
Nature Communications, 2016Co-Authors: Natalie K. Lee, Nicole H. Wilson, Amanda White, Ka Wai Fok, Conor J Oleary, Hayley L Cox, Magdalene Michael, Alpha S Yap, Helen M. CooperAbstract:To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the actin nucleation machinery governing junctional stability. Loss of Neogenin perturbs AJs and attenuates junctional tension. Neogenin promotes actin nucleation at AJs by recruiting the Wave regulatory complex (WRC) and Arp2/3. A direct interaction between the Neogenin WIRS domain and the WRC is crucial for the spatially restricted recruitment of the WRC to the junction. Thus, we provide the first example of a functional WIRS-WRC interaction in epithelia. We further show that Neogenin regulates cadherin recycling at the AJ. In summary, we identify Neogenin as a pivotal component of the AJ, where it influences both cadherin dynamics and junctional tension.
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Neogenin and rgma control neural tube closure and neuroepithelial morphology by regulating cell polarity
The Journal of Neuroscience, 2008Co-Authors: Nigel Kee, Nicole H. Wilson, Brian Key, Melissa De Vries, Danakai Bradford, Helen M. CooperAbstract:In humans, neural tube closure defects occur in 1:1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel signaling pathway essential for radial intercalation and epithelialization during neural fold elevation and neural tube morphogenesis.
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Overexpression of repulsive guidance molecule (RGM) a induces cell death through Neogenin in early vertebrate development
Journal of Molecular Histology, 2008Co-Authors: Grace J. Shin, Nicole H. WilsonAbstract:Repulsive guidance molecule (RGM) a is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein that has been implicated in chemorepulsive axon guidance. Although RGMa binds the transmembrane receptor Neogenin, the developmental events controlled by the RGMa-Neogenin interactions in vivo remain largely unknown. We have cloned full-length RGMa from Xenopus borealis for the first time and identified two homologous genes referred to as RGMa1 and RGMa2. Here we show RGMa1 overexpression at 2-cell-stage resulted in cell death, which lead to an early embryonic lethal phenotype of the embryos. Time-lapse photomicroscopy revealed that embryos began to show initial morphological defects from ∼5 h post-fertilization (hpf) which was then followed by extensive blastomere cell death at ∼11 hpf. This phenotype was rescued by simultaneous knock down of RGMa using translation blocking anti-sense morpholinos. Knock down of the RGMa1 receptor Neogenin in RGMa1 overexpressing embryos was also able to rescue the phenotype. Together these results indicated that RGMa1 was signalling through Neogenin to induce cell death in the early embryo. While previous studies have suggested that Neogenin is a dependence receptor that induces cell death in the absence of RGM, we have instead shown that Neogenin-RGM interactions induce cell death in the early embryo. The roles of RGMa1 and Neogenin appear to be context specific so that their co-ordinated and regulated expressions are essential for normal development of the vertebrate embryo.
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Neogenin: one receptor, many functions.
The International Journal of Biochemistry & Cell Biology, 2007Co-Authors: Nicole H. Wilson, Brian KeyAbstract:Neogenin is a multifunctional transmembrane receptor belonging to the immunoglobulin superfamily. It displays identical secondary structure to deleted in colorectal cancer (DCC), a netrin receptor that is involved in axon guidance and cell survival. Like DCC, Neogenin is able to transduce signals elicited by netrin. These Neogenin-netrin interactions have been implicated in tissue morphogenesis, angiogenesis, myoblast differentiation and most recently in axon guidance. Neogenin is also a receptor for repulsive guidance molecule, a glycosylphosphatidylinositol-linked protein involved in neuronal differentiation, apoptosis and repulsive axon guidance. Numerous studies have been started to elucidate the in vivo functions of Neogenin, and its role in multiple aspects of development and homeostasis.
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Neogenin interacts with rgma and netrin 1 to guide axons within the embryonic vertebrate forebrain
Developmental Biology, 2006Co-Authors: Nicole H. Wilson, Brian KeyAbstract:In the embryonic forebrain, pioneer axons establish a simple topography of dorsoventral and longitudinal tracts. The cues used by these axons during the initial formation of the axon scaffold remain largely unknown. We have investigated the axon guidance role of Neogenin, a member of the immunoglobulin (Ig) superfamily that binds to the chemoattractive ligand Netrin-1, as well as to the chemorepulsive ligand repulsive guidance molecule (RGMa). Here, we show strong expression of Neogenin and both of its putative ligands in the developing Xenopus forebrain. Neogenin loss-of-function mutants revealed that this receptor was essential for axon guidance in an early forming dorsoventral brain pathway. Similar mutant phenotypes were also observed following loss of either RGMa or Netrin-1. Simultaneous partial knock downs of these molecules revealed dosage-sensitive interactions and confirmed that these receptors and ligands were acting in the same pathway. The results provide the first evidence that Neogenin acts as an axon guidance molecule in vivo and support a model whereby Neogenin-expressing axons respond to a combination of attractive and repulsive cues as they navigate their ventral trajectory.
Alain Chédotal - One of the best experts on this subject based on the ideXlab platform.
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repulsive guidance molecule Neogenin a novel ligand receptor system playing multiple roles in neural development
Development Growth & Differentiation, 2004Co-Authors: Eiji Matsunaga, Alain ChédotalAbstract:The repulsive guidance molecule (RGM) is a membrane-bound protein originally isolated as an axon guidance molecule in the visual system. Recently, the transmembrane protein, Neogenin, has been identified as the RGM receptor. In vitro analysis with retinal explants showed that RGM repels temporal retinal axons and collapses their growth cones through Neogenin-mediated signaling. However, RGM and Neogenin are also broadly expressed at the early embryonic stage, suggesting that they do not only control the guidance of visual axons. Gene expression perturbation experiments in chick embryos showed that Neogenin induces cell death, and its ligand, RGM, blocks the pro-apoptotic activity of Neogenin. Thus, RGM/Neogenin is a novel dependence ligand/receptor couple as well as an axon guidance molecular complex.
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RGM and its receptor Neogenin regulate neuronal survival
Nature cell biology, 2004Co-Authors: Eiji Matsunaga, Bernhard K. Mueller, Philippe P. Monnier, Servane Tauszig-delamasure, Stephen M. Strittmatter, Patrick Mehlen, Alain ChédotalAbstract:Repulsive guidance molecule (RGM) is an axon guidance protein that repels retinal axons upon activation of the Neogenin receptor. To understand the functions of RGM-Neogenin complexes in vivo, we used gene transfer technology to perturb their expression in the developing neural tube of chick embryos. Surprisingly, Neogenin over-expression or RGM down-expression in the neural tube induces apoptosis. Neogenin pro-apoptotic activity in immortalized neuronal cells and in the neural tube is associated with the cleavage of its cytoplasmic domain by caspases. Thus Neogenin is a dependence receptor inducing cell death in the absence of RGM, whereas the presence of RGM inhibits this effect.
