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Yves-alain Barde - One of the best experts on this subject based on the ideXlab platform.
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Seizure-induced neuronal death is suppressed in the absence of the endogenous lectin galectin-1.
Journal of Neuroscience, 2012Co-Authors: Vincent Bischoff, Rubén Deogracias, Françoise Poirier, Yves-alain BardeAbstract:Pilocarpine injection induces epileptic seizures in rodents, an experimental paradigm extensively used to model temporal lobe epilepsy in humans. It includes conspicuous neuronal death in the forebrain and previous work has demonstrated an involvement of the Neurotrophin Receptor P75(NTR) in this process. Following the identification of Galectin-1 (Gal-1) as a downstream effector of P75(NTR), we examine here the role of this endogenous lectin in pilocarpine-induced cell death in adult mice. We found that most somatostatin-positive neurons also express Gal-1 and that in mice lacking the corresponding gene Lgals1, pilocarpine-induced neuronal death was essentially abolished in the forebrain. We also found that the related lectin Galectin-3 (Gal-3) was strongly upregulated by pilocarpine in microglial cells. This upregulation was absent in Lgals1 mutants and our results with Lgals3-null animals show that Gal-3 is not required for neuronal death in the hippocampus. These findings provide new insights into the roles and regulation of endogenous lectins in the adult CNS and a surprisingly selective proapoptotic role of Gal-1 for a subpopulation of GABAergic interneurons.
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the Neurotrophin Receptor P75 ntr novel functions and implications for diseases of the nervous system
Nature Neuroscience, 2002Co-Authors: Georg Dechant, Yves-alain BardeAbstract:Neurotrophins have long been known to promote the survival and differentiation of vertebrate neurons. However, these growth factors can also induce cell death through the P75 Neurotrophin Receptor (P75(NTR)), a member of the tumor necrosis factor Receptor superfamily. Consistent with a function in controlling the survival and process formation of neurons, P75(NTR) is mainly expressed during early neuronal development. In the adult, P75(NTR) is re-expressed in various pathological conditions, including epilepsy, axotomy and neurodegeneration. Potentially toxic peptides, including the amyloid beta- (Abeta-) peptide that accumulates in Alzheimer's disease, are ligands for P75(NTR). Recent work also implicates P75(NTR) in the regulation of both synaptic transmission and axonal elongation. It associates with the Nogo Receptor, a binding protein for axonal growth inhibitors, and appears to be the transducing subunit of this Receptor complex.
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the Neurotrophin Receptor P75 ntr novel functions and implications for diseases of the nervous system
Nature Neuroscience, 2002Co-Authors: Georg Dechant, Yves-alain BardeAbstract:Neurotrophins have long been known to promote the survival and differentiation of vertebrate neurons. However, these growth factors can also induce cell death through the P75 Neurotrophin Receptor (P75NTR), a member of the tumor necrosis factor Receptor superfamily. Consistent with a function in controlling the survival and process formation of neurons, P75NTR is mainly expressed during early neuronal development. In the adult, P75NTR is re-expressed in various pathological conditions, including epilepsy, axotomy and neurodegeneration. Potentially toxic peptides, including the amyloid - (A-) peptide that accumulates in Alzheimer's disease, are ligands for P75NTR. Recent work also implicates P75NTR in the regulation of both synaptic transmission and axonal elongation. It associates with the Nogo Receptor, a binding protein for axonal growth inhibitors, and appears to be the transducing subunit of this Receptor complex.
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the zinc finger protein nrif interacts with the Neurotrophin Receptor P75ntr and participates in programmed cell death
The EMBO Journal, 1999Co-Authors: Elisabeth Casademunt, Jose Maria Frade, Bruce D. Carter, Georg Dechant, Isabel Benzel, Yves-alain BardeAbstract:NRIF (Neurotrophin Receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Kruppel family which interacts with the Neurotrophin Receptor P75(NTR). The interaction was first detected in yeast and then biochemically confirmed using recombinant GST-NRIF fusions and P75(NTR) expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the P75(NTR)-binding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F(2 )generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif(-/-) mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in P75(NTR)/NGF-mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in P75(NTR)(-/-) and ngf(-/-) mice. These results indicate that NRIF is an intracellular P75(NTR)-binding protein transducing cell death signals during development.
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genetic evidence for cell death mediated by nerve growth factor and the Neurotrophin Receptor P75 in the developing mouse retina and spinal cord
Development, 1999Co-Authors: Jose Maria Frade, Yves-alain BardeAbstract:The role of nerve growth factor (NGF) and of the Neurotrophin Receptor P75 (P75(NTR)) in programmed cell death was investigated in the retina and the spinal cord of mouse embryos. Large numbers of cells express P75(NTR) in and along the developing optic nerve and in the mantle zone of the spinal cord. In embryos carrying deletions in the ngf or the P75(NTR) gene, cell death was reduced in the retina and in the spinal cord. Increased numbers of Islet-1-immunoreactive cells were detected in the dorsal spinal cord, and the mantle zone was enlarged in both mutants. These results indicate that NGF/P75(NTR)-dependent mechanisms are used to remove cells when axonal tracts elongate in developing neuroepithelia.
Shigeru Yasumoto - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophin Receptor P75 ntr characterizes human esophageal keratinocyte stem cells in vitro
Oncogene, 2003Co-Authors: Tomoyuki Okumura, Yutaka Shimada, Masayuki Imamura, Shigeru YasumotoAbstract:We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity Neurotrophin Receptor P75NTR and differentially expressed cell adhesion molecules, the β1 and β4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the P75NTR-positive cell subset is immature relative to the other predominant subpopulations coexpressing β1 integrin at higher levels. The P75NTR-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the P75NTR-positive cell subset. These findings strongly implicate P75NTR as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.
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Neurotrophin Receptor P75 ntr characterizes human esophageal keratinocyte stem cells in vitro
Oncogene, 2003Co-Authors: Tomoyuki Okumura, Yutaka Shimada, Masayuki Imamura, Shigeru YasumotoAbstract:We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity Neurotrophin Receptor P75(NTR) and differentially expressed cell adhesion molecules, the beta1 and beta4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the P75(NTR)-positive cell subset is immature relative to the other predominant subpopulations coexpressing beta1 integrin at higher levels. The P75(NTR)-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the P75(NTR)-positive cell subset. These findings strongly implicate P75(NTR) as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.
Elizabeth J Coulson - One of the best experts on this subject based on the ideXlab platform.
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Removal of P75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-β Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice
Molecular Neurobiology, 2019Co-Authors: Lei Qian, Stephanie Shepheard, Marylouise Rogers, Michael R. Milne, Rodrigo Medeiros, Elizabeth J CoulsonAbstract:The degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer’s disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the P75 Neurotrophin Receptor (P75^NTR), which mediates cell death, and the extracellular domain of P75^NTR can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal P75^NTR to the progression of AD by removing P75^NTR from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of P75^NTR slowed cognitive decline and reduced both Aβ accumulation into plaques and gliosis. Expression of the amyloid protein precursor and its cleavage enzymes ADAM10 and BACE1 were unchanged. There was also no upregulation of P75^NTR in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed P75^NTR and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of P75^NTR from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, Aβ clearance mechanisms.
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an intracellular domain fragment of the P75 Neurotrophin Receptor P75 ntr enhances tropomyosin Receptor kinase a trka Receptor function
Journal of Biological Chemistry, 2013Co-Authors: Dusan Matusica, Alex M Sykes, Sune Skeldal, Nickless Palstra, Aanchal Sharma, Elizabeth J CoulsonAbstract:Facilitation of nerve growth factor (NGF) signaling by the P75 Neurotrophin Receptor (P75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between P75(NTR) and TrkA Receptors required for this activity is not understood. Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of P75(NTR) interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of P75(NTR) (P75(ICD)) containing these 29 amino acids is produced by regulated proteolysis of the full-length Receptor. We demonstrate that generation of this fragment is a requirement for P75(NTR) to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of P75(ICD) acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which P75(NTR) and TrkA interact to enhance neurotrophic signaling.
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proteolytic processing of the P75 Neurotrophin Receptor a prerequisite for signalling neuronal life growth and death signalling are crucially regulated by intra membrane proteolysis and trafficking of P75 ntr
BioEssays, 2011Co-Authors: Sune Skeldal, Dusan Matusica, Anders Nykjaer, Elizabeth J CoulsonAbstract:The common Neurotrophin Receptor (P75(NTR) ) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by P75(NTR) -mediated signals following activation by either mature or pro-Neurotrophins and in combination with various co-Receptors, including Trk Receptors and sortilin. Here, we review the known functions of P75(NTR) by cell type, Receptor-ligand combination, and whether regulated intra-membrane proteolysis of P75(NTR) is required for signalling. We highlight that the generation of the intracellular domain fragment of P75(NTR) is associated with many of the Receptor functions, regardless of its ligand and co-Receptor interactions.
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aβ1 42 stimulates adult svz neurogenesis through the P75 Neurotrophin Receptor
Neurobiology of Aging, 2009Co-Authors: Areechun Sotthibundhu, Wipawan Thangnipon, Elizabeth J CoulsonAbstract:The generation of amyloid-beta peptide (A) and its accumulation in amyloid plaques are generally recognized as key characteristics of Alzheimer’s disease. A number of reports have indicated that A can regulate the proliferation of neural precursor cells and adult neurogenesis, suggesting that this may underpin the cognitive decline and compromised olfaction also associated with the condition. Here we report that A1–42 treatment both in vitro and in vivo, as well as endogenous generation of A in C100 and APP/PS1 transgenic models of Alzheimer’s disease, stimulate neurogenesis of young adult subventricular zone precursors. The neurogenic effect of A1–42 was found to require expression of the P75 Neurotrophin Receptor (P75 NTR ) by the precursor cells, and activation of P75 NTR by metalloprotease cleavage. However, precursors from 12-month-old APP/PS1 mice failed to respond to A1–42. Our results suggest that overstimulation of P75 NTR -positive progenitors during early life might result in depletion of the stem cell pool and thus a more rapid decline in basal neurogenesis. This, in turn, could lead to impaired neurogenic function in later life. © 2008 Elsevier Inc. All rights reserved.
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the P75 Neurotrophin Receptor regulates hippocampal neurogenesis and related behaviours
European Journal of Neuroscience, 2008Co-Authors: Vibeke S Catts, Noura Almenhali, Thomas H J Burne, Michael J Colditz, Elizabeth J CoulsonAbstract:Although changes to neural circuitry are believed to underlie behavioural characteristics mediated by the hippocampus, the contribution of neurogenesis to this process remains controversial. This is partially because the molecular regulators of neurogenesis remain to be fully elucidated, and experiments generically preventing neurogenesis have, for the most part, depended on paradigms involving irradiation. Here we show that mice lacking the P75 Neurotrophin Receptor (P75(NTR-/-)) have 25% fewer neuroblasts and 50% fewer newborn neurons in the dentate gyrus, coincident with increased rates of cell death of newly born cells and a significantly smaller granular cell layer and dentate gyrus, than those of P75(NTR+/+) mice. Whereas P75(NTR-/-) mice had increased latency to feed in a novelty-suppressed feeding paradigm they had increased mobility in another test of "depression", the tail-suspension test. P75(NTR-/-) mice also had subtle behavioural impairment in Morris water maze tasks compared to wild-type animals. No difference between genotypes was found in relation to anxiety or exploration behaviour based on the elevated-plus maze, light-dark, hole-board, T-maze or forced-swim tests. Overall, this study demonstrates that P75(NTR) is an important regulator of hippocampal neurogenesis, with concomitant effects on associated behaviours. However, the behavioural attributes of the P75(NTR-/-) mice may be better explained by altered circuitry driven by the loss of P75(NTR) in the basal forebrain, rather than direct changes to neurogenesis.
Tomoyuki Okumura - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophin Receptor P75 ntr characterizes human esophageal keratinocyte stem cells in vitro
Oncogene, 2003Co-Authors: Tomoyuki Okumura, Yutaka Shimada, Masayuki Imamura, Shigeru YasumotoAbstract:We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity Neurotrophin Receptor P75NTR and differentially expressed cell adhesion molecules, the β1 and β4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the P75NTR-positive cell subset is immature relative to the other predominant subpopulations coexpressing β1 integrin at higher levels. The P75NTR-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the P75NTR-positive cell subset. These findings strongly implicate P75NTR as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.
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Neurotrophin Receptor P75 ntr characterizes human esophageal keratinocyte stem cells in vitro
Oncogene, 2003Co-Authors: Tomoyuki Okumura, Yutaka Shimada, Masayuki Imamura, Shigeru YasumotoAbstract:We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity Neurotrophin Receptor P75(NTR) and differentially expressed cell adhesion molecules, the beta1 and beta4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the P75(NTR)-positive cell subset is immature relative to the other predominant subpopulations coexpressing beta1 integrin at higher levels. The P75(NTR)-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the P75(NTR)-positive cell subset. These findings strongly implicate P75(NTR) as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.
Jose Maria Frade - One of the best experts on this subject based on the ideXlab platform.
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genetic evidence for P75ntr dependent tetraploidy in cortical projection neurons from adult mice
The Journal of Neuroscience, 2013Co-Authors: Noelia Lopezsanchez, Jose Maria FradeAbstract:A subpopulation of chick retinal projection neurons becomes tetraploid during development, an event prevented by blocking antibodies against P75 Neurotrophin Receptor (P75(NTR)). We have used an optimized flow cytometric assay, based on the analysis of unfixed brain cell nuclei, to study whether P75(NTR)-dependent neuronal tetraploidization takes place in the cerebral cortex, giving rise to projection neurons as well. We show that 3% of neurons in both murine neocortex and chick telencephalic derivatives are tetraploid, and that in the mouse ~85% of these neurons express the immediate early genes Erg-1 and c-Fos, indicating that they are functionally active. Tetraploid cortical neurons (65-80%) express CTIP2, a transcription factor specific for subcortical projection neurons in the mouse neocortex. During the period in which these neurons are born, P75(NTR) is detected in differentiating neurons undergoing DNA replication. Accordingly, P75(NTR)-deficient mice contain a reduced proportion of both NeuN and CTIP2-positive neocortical tetraploid neurons, thus providing genetic evidence for the participation of P75(NTR) in the induction of neuronal tetraploidy in the mouse neocortex. In the striatum tetraploidy is mainly associated with long-range projection neurons as well since ~80% of tetraploid neurons in this structure express calbindin, a marker of neostriatal-matrix spiny neurons, known to establish long-range projections to the substantia nigra and globus pallidus. In contrast, only 20% of tetraploid cortical neurons express calbindin, which is mainly expressed in layers II-III, where CTIP2 is absent. We conclude that tetraploidy mainly affects long-range projection neurons, being facilitated by P75(NTR) in the neocortex.
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somatic tetraploidy in vertebrate neurons implications in physiology and pathology
Communicative & Integrative Biology, 2010Co-Authors: Jose Maria FradeAbstract:The presence of polyploid neurons in the vertebrate nervous system has been a subject of debate since the 1960s. At that time, Purkinje cells were proposed to be tetraploid, but technical limitations impeded to reach a clear conclusion, and the current believe is that most vertebrate neurons are diploid. By using up-to-date approaches we have recently demonstrated the existence of a subpopulation of tetraploid retinal ganglion cells (RGCs) in the vertebrate retina. In the chick, these neurons show large somas and extensive dendritic trees and most of them express a marker specific of RGCs innervating a specific lamina of the optic tectum. We have also demonstrated that these neurons are generated in response to nerve growth factor (NGF) acting through the Neurotrophin Receptor P75 (P75NTR), which induces E2F1 activity and cell cycle re-entry in migrating RGC neuroblasts lacking retinoblastoma (Rb) protein. We have also showed that brain-derived neurotrophic factor (BDNF) prevents G2/M transition in the te...
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somatic tetraploidy in specific chick retinal ganglion cells induced by nerve growth factor
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Sandra M Morillo, Pedro Escoll, Antonio De La Hera, Jose Maria FradeAbstract:A subset of neurons in the normal vertebrate nervous system contains double the normal amount of DNA in their nuclei. These neurons are all thought to derive from aberrant mitoses in neuronal precursor cells. Here we show that endogenous NGF induces DNA replication in a subpopulation of differentiating chick retinal ganglion cells that express both the Neurotrophin Receptor P75 and the E2F1 transcription factor, but that lack the retinoblastoma protein. Many of these neurons avoid G2/M transition and remain alive in the retina as tetraploid cells with large cell somas and extensive dendritic trees, and most of them express β2 nicotinic acetylcholine Receptor subunits, a specific marker of retinal ganglion cells innervating lamina F in the stratum-griseum-et-fibrosum-superficiale of the tectal cortex. Tetraploid neurons were also observed in the adult mouse retina. Thus, a developmental program leading to somatic tetraploidy in specific retinal neurons exists in vertebrates. This program might occur in other vertebrate neurons during normal or pathological situations.
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the zinc finger protein nrif interacts with the Neurotrophin Receptor P75ntr and participates in programmed cell death
The EMBO Journal, 1999Co-Authors: Elisabeth Casademunt, Jose Maria Frade, Bruce D. Carter, Georg Dechant, Isabel Benzel, Yves-alain BardeAbstract:NRIF (Neurotrophin Receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Kruppel family which interacts with the Neurotrophin Receptor P75(NTR). The interaction was first detected in yeast and then biochemically confirmed using recombinant GST-NRIF fusions and P75(NTR) expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the P75(NTR)-binding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F(2 )generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif(-/-) mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in P75(NTR)/NGF-mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in P75(NTR)(-/-) and ngf(-/-) mice. These results indicate that NRIF is an intracellular P75(NTR)-binding protein transducing cell death signals during development.
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genetic evidence for cell death mediated by nerve growth factor and the Neurotrophin Receptor P75 in the developing mouse retina and spinal cord
Development, 1999Co-Authors: Jose Maria Frade, Yves-alain BardeAbstract:The role of nerve growth factor (NGF) and of the Neurotrophin Receptor P75 (P75(NTR)) in programmed cell death was investigated in the retina and the spinal cord of mouse embryos. Large numbers of cells express P75(NTR) in and along the developing optic nerve and in the mantle zone of the spinal cord. In embryos carrying deletions in the ngf or the P75(NTR) gene, cell death was reduced in the retina and in the spinal cord. Increased numbers of Islet-1-immunoreactive cells were detected in the dorsal spinal cord, and the mantle zone was enlarged in both mutants. These results indicate that NGF/P75(NTR)-dependent mechanisms are used to remove cells when axonal tracts elongate in developing neuroepithelia.