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Eric M Shooter - One of the best experts on this subject based on the ideXlab platform.
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neurotrophins regulate schwann cell migration by activating divergent signaling pathways dependent on rho gtpases
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Junji Yamauchi, Jonah R Chan, Eric M ShooterAbstract:Neurotrophins are recognized widely as essential factors in the developing nervous system. Previously, we demonstrated that neurotrophin 3 activation of TrkC inhibits Schwann cell myelination and enhances the migration of primary Schwann cells through the signaling pathway regulated by the Rho GTPases Rac1 and Cdc42. Here, we show that neurotrophins activate divergent signaling pathways to promote or inhibit Schwann cell migration. Endogenous brain-derived neurotrophic factor acting through p75NTR inhibits Schwann cell migration dramatically by Src kinase-dependent activation of the guanine-nucleotide exchange factor Vav2 and RhoA. Together, these results suggest that neurotrophins and their receptors differentially regulate Schwann cell migration through the signaling pathways that depend on Rho GTPases.
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Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Junji Yamauchi, Jonah R Chan, Eric M ShooterAbstract:During development and nerve injury, complex interactions between glial cells and neurons are essential for establishing proper nerve function. Neurotrophins play multiple roles in the developing nervous system, including cell survival, growth, and differentiation. Here we show that migration of Schwann cells, isolated from sciatic nerves, is significantly enhanced by neurotrophin 3, but not by nerve growth factor or brain-derived neurotrophic factor. The Neurotrophin-3-induced cell migration was also observed in Schwann cells isolated from sciatic nerves of p75NTR-/- mice, indicating that neurotrophin 3 enhances cell migration through TrkC. This effect was blocked by K252a, an inhibitor of the Trk receptor family. Additionally, the Neurotrophin-3-induced cell migration depended on Rho GTPases (Rac1 and Cdc42) and c-Jun N-terminal kinase. We obtained the same results with Cos-7 cells expressing TrkC. Taken together, these results suggest that neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase signaling pathway.
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the neurotrophin receptor p75ntr as a positive modulator of myelination
Science, 2002Co-Authors: Jose Miguel Cosgaya, Jonah R Chan, Eric M ShooterAbstract:Schwann cells in developing and regenerating peripheral nerves express elevated levels of the neurotrophin receptor p75 NTR . Neurotrophins are key mediators of peripheral nervous system myelination. Our results show that myelin formation is inhibited in the absence of functional p75 NTR and enhanced by blocking TrkC activity. Moreover, the enhancement of myelin formation by endogenous brain-derived neurotrophic factor is mediated by the p75 NTR receptor, whereas TrkC receptors are responsible for Neurotrophin-3 inhibition. Thus p75 NTR and TrkC receptors have opposite effects on myelination.
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p75 reduces TrkB tyrosine autophosphorylation in response to brain-derived neurotrophic factor and neurotrophin 4/5.
Journal of Biological Chemistry, 2000Co-Authors: Jouni Vesa, Alex Krüttgen, Eric M ShooterAbstract:Abstract Neurotrophins mediate their signals through two different receptors: the family of receptor tyrosine kinases, Trks, and the low affinity pan-neurotrophin receptor p75. Trk receptors show more restricted ligand specificity, whereas all neurotrophins are able to bind to p75. One important function of p75 is the enhancement of nerve growth factor signaling via TrkA by increasing TrkA tyrosine autophosphorylation. Here, we have examined the importance of p75 on TrkB- and TrkC-mediated neurotrophin signaling in an MG87 fibroblast cell line stably transfected with either p75 and TrkB or p75 and TrkC, as well as in PC12 cells stably transfected with TrkB. In contrast to TrkA signaling, p75 had a negative effect on TrkB tyrosine autophosphorylation in response to its cognate neurotrophins, brain-derived neurotrophic factor and neurotrophin 4/5. On the other hand, p75 had no effect on TrkB or TrkC activation in neurotrophin 3 treatment. p75 did not effect extracellular signal-regulated kinase 2 tyrosine phosphorylation in response to brain-derived neurotrophic factor, neurotrophin 3, or neurotrophin 4/5. These results suggest that the observed reduction in TrkB tyrosine autophosphorylation caused by p75 does not influence Ras/mitogen-activated protein kinase signaling pathway in neurotrophin treatments.
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Neurotrophins induce release of neurotrophins by the regulated secretory pathway
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Alex Krüttgen, J. Carsten Möller, John Victor Heymach, Eric M ShooterAbstract:Recent studies have established that neurotrophin synthesis and secretion are regulated by activity and that these factors are involved in activity-dependent processes in the nervous system. Neurotrophins also are known to induce increases in intracellular calcium, a trigger for regulated secretion. This finding raises the possibility that neurotrophins themselves may stimulate regulated secretion of neurotrophins. To address this question, we studied the release of neurotrophins from transfected PC12 cells, a widely used model for neuronal secretion and neurotrophin signal transduction. We found that neurotrophins induced the regulated secretion of brain-derived neurotrophic factor, Neurotrophin-3 (NT-3), and neurotrophin-4/5. The effect of brain-derived neurotrophic factor on release of NT-3 could be abolished by REX, a p75 blocking antibody, but not by K252a, an inhibitor of neurotrophin tyrosine kinase receptor (Trk) signaling. The nerve growth factor effect on release of NT-3 could be blocked only by simultaneous application of REX and K252a, suggesting that they are mediated by TrkA as well as p75. Our data show that neurotrophins are able to induce the regulated secretion of neurotrophins and suggest a signal-transducing role for both TrkA and p75 in this process. The neurotrophin-induced release of neurotrophins may be relevant for activity-dependent processes such as synaptic plasticity and memory formation.
Kalipada Pahan - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb implications for alzheimer disease therapy
Journal of Biological Chemistry, 2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Abstract Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser133) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb
2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Background: Increase in neurotrophic factors in the brain is a possible therapeutic approach for different neurodegenerative disorders. Results: Sodium phenylbutyrate, an FDA-approved drug for hyperammonemia, increases neurotrophic factors in brain cells via the PKC-CREB pathway. Conclusion: These results delineate a novel neurotrophic property of sodium phenylbutyrate. Significance: Sodium phenylbutyrate may be of therapeutic benefit in neurodegenerative disorders. Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser 133 ) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by antiTrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD. Neurotrophins are a class of small, dimeric growth factors essential for the development, maintenance, and function of the
Grant T Corbett - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb implications for alzheimer disease therapy
Journal of Biological Chemistry, 2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Abstract Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser133) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.
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sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb
2013Co-Authors: Grant T Corbett, Kalipada PahanAbstract:Background: Increase in neurotrophic factors in the brain is a possible therapeutic approach for different neurodegenerative disorders. Results: Sodium phenylbutyrate, an FDA-approved drug for hyperammonemia, increases neurotrophic factors in brain cells via the PKC-CREB pathway. Conclusion: These results delineate a novel neurotrophic property of sodium phenylbutyrate. Significance: Sodium phenylbutyrate may be of therapeutic benefit in neurodegenerative disorders. Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser 133 ) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by antiTrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD. Neurotrophins are a class of small, dimeric growth factors essential for the development, maintenance, and function of the
J H Gilmore - One of the best experts on this subject based on the ideXlab platform.
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Nerve growth factor, brain-derived neurotrophic factor, and Neurotrophin-3 levels in human amniotic fluid.
American journal of obstetrics and gynecology, 1999Co-Authors: C E Marx, B J Vance, L F Jarskog, N C Chescheir, J H GilmoreAbstract:Neurotrophins are proteins that promote neuronal growth and differentiation. In this pilot study we determined whether the neurotrophins nerve growth factor, brain-derived neurotrophic factor, and Neurotrophin-3 were present in amniotic fluid specimens to begin to elucidate their developmental regulation. We also explored associations between neurotrophin levels and central nervous system abnormalities and exposure to infection. One hundred thirty-four amniotic fluid specimens were obtained from women undergoing amniocentesis at University of North Carolina Hospitals. Each specimen was assayed by enzyme-linked immunosorbent assay for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Associations of maternal age, gestational age, and maternal ethnicity with neurotrophin levels were explored. Neurotrophin levels in pregnancies in which there was enlargement of the fetal cerebral lateral ventricles or exposure to infection were compared with those in control pregnancies. Spearman correlational analyses and analyses of covariance were performed, with adjustment for gestational age. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 were detected in all amniotic fluid specimens. Nerve growth factor increased with gestational age (P =.045). Brain-derived neurotrophic factor decreased with gestational age (P =.035). Patients with ventriculomegaly (with or without other central nervous system abnormalities) on ultrasonographic examination (n = 6) had significantly lower nerve growth factor levels than control subjects (P =.0046); patients with evidence of infection (n = 5) during pregnancy had significantly lower nerve growth factor (P =.0037) and brain-derived neurotrophic factor (P =.0362) levels. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 are detectable in amniotic fluid and vary with gestational age. Decreased nerve growth factor and brain-derived neurotrophic factor levels in amniotic fluid may be a marker for the presence of central nervous system abnormalities, infectious insults in utero, or both.
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Nerve growth factor, brain-derived neurotrophic factor, and Neurotrophin-3 levels in human amniotic fluid.
American Journal of Obstetrics and Gynecology, 1999Co-Authors: C E Marx, B J Vance, L F Jarskog, N C Chescheir, J H GilmoreAbstract:Abstract Objective: Neurotrophins are proteins that promote neuronal growth and differentiation. In this pilot study we determined whether the neurotrophins nerve growth factor, brain-derived neurotrophic factor, and Neurotrophin-3 were present in amniotic fluid specimens to begin to elucidate their developmental regulation. We also explored associations between neurotrophin levels and central nervous system abnormalities and exposure to infection. Study Design: One hundred thirty-four amniotic fluid specimens were obtained from women undergoing amniocentesis at University of North Carolina Hospitals. Each specimen was assayed by enzyme-linked immunosorbent assay for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Associations of maternal age, gestational age, and maternal ethnicity with neurotrophin levels were explored. Neurotrophin levels in pregnancies in which there was enlargement of the fetal cerebral lateral ventricles or exposure to infection were compared with those in control pregnancies. Spearman correlational analyses and analyses of covariance were performed, with adjustment for gestational age. Results: Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 were detected in all amniotic fluid specimens. Nerve growth factor increased with gestational age ( P = .045). Brain-derived neurotrophic factor decreased with gestational age ( P = .035). Patients with ventriculomegaly (with or without other central nervous system abnormalities) on ultrasonographic examination (n = 6) had significantly lower nerve growth factor levels than control subjects ( P = .0046); patients with evidence of infection (n = 5) during pregnancy had significantly lower nerve growth factor ( P = .0037) and brain-derived neurotrophic factor ( P = .0362) levels. Conclusions: Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 are detectable in amniotic fluid and vary with gestational age. Decreased nerve growth factor and brain-derived neurotrophic factor levels in amniotic fluid may be a marker for the presence of central nervous system abnormalities, infectious insults in utero, or both. (Am J Obstet Gynecol 1999;181:1125-30.)
Gary R Lewin - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophin-4: A Survival Factor for Adult Sensory Neurons
Current Biology, 2002Co-Authors: Cheryl L. Stucky, Jung-bum Shin, Gary R LewinAbstract:Abstract The nerve growth factor (NGF) family of neurotrophins provides a substantial part of the normal trophic support for sensory neurons during development [1]. Although these neurotrophins, which include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4), continue to be expressed into adulthood [2, 3], there is little evidence that they are survival factors for adult neurons [4]. Here we have examined the age-dependent neurotrophic requirements of a specialized type of mechanoreceptive neuron, called a D-hair receptor, in the dorsal root ganglion (DRG). Studies using knockout mice have demonstrated that the survival of D-hair receptors is dependent upon both NT-3 and NT-4 [5–7]. Here, we show that the time period when D-hair receptors require these two neurotrophins is different. Survival of D-hair receptors depends on NT-3 early in postnatal development and NT-4 later in the mature animal. The age-dependent loss of D-hair neurons in older NT-4 knockout mice was accompanied by a large reduction (78%) in neurons positive for the NT-4 receptor (trkB) together with neuronal apoptosis in the DRG. This is the first evidence that sensory neurons have a physiological requirement for a single neurotrophin for their continued survival in the adult.
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Neurotrophins and the Specification of Neuronal Phenotype
Philosophical Transactions of the Royal Society B, 1996Co-Authors: Gary R LewinAbstract:Nerve growth factor, brain derived neurotrophic factor and Neurotrophin-3 all influence sensory neurons derived from the dorsal root ganglia. Traditionally these neurotrophins have been thought of as survival factors for sensory neurons during their development. Recent evidence from experiments where the in vivo levels of these proteins has been manipulated indicates that they may influence the development of specific sensory neuron phenotypes. In this review these experiments are discussed in relation to the mechanisms by which neurotrophins could influence the phenotypic fate of sensory neurons. The first mechanism requires that when a neuron becomes dependent for survival on a neurotrophin the availability of the factor simply influences the number of neurons surviving with a certain modality. This model requires that neurotrophin repsonsiveness is a determinant of the possible modalities that the neuron may acquire. The second mechanism requires that the availability of a given neurotrophin influences how many neurons can differentiate into different sensory neuron phenotype independent of survival. The available experimental data is discussed in relation to these two models.
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Roles of Neurotrophin-3 during Early Development of the Peripheral Nervous System
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 1996Co-Authors: M. Ockel, Gary R Lewin, D. Von Schack, A. Schropel, Georg Dechant, Yves-alain BardeAbstract:The neurotrophins are structurally related proteins regulating cell numbers in the developing vertebrate nervous system. They are necessary survival factors preventing the death of specific neuronal populations. Previous experiments have indicated that the administration of nerve growth factor or of brain-derived neurotrophic factor during the formation of sensory ganglia and of target innervation increases the number of neurons by preventing normally occurring neuronal death. These results support the view that during development, neuronal numbers are adjusted to the size of the target tissue by the release of limiting amounts of neurotrophins. However, increasing the levels of Neurotrophin-3 during the formation of sensory ganglia results in a marked decrease in neuronal numbers, possibly as a consequence of premature cessation of sensory neuroblast proliferation. In sympathetic ganglia, the application of Neurotrophin-3 during the formation of the sympathetic chain causes cell numbers to increase, a result also observed following the application of nerve growth factor. It thus appears that Neurotrophin-3 and nerve growth factor can regulate cell numbers well before the period of target-derived control, and that Neurotrophin-3 affects neuronal numbers in sensory and sympathetic ganglia in opposite ways.
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In vivo effects of Neurotrophin-3 during sensory neurogenesis.
Development (Cambridge England), 1996Co-Authors: M. Ockel, Gary R Lewin, Yves-alain BardeAbstract:The neurotrophins nerve growth factor, brain-derived neurotrophic factor and Neurotrophin-3 are structurally related proteins regulating the number of neurons in peripheral ganglia of the nervous system. Increased levels of nerve growth factor or of brain-derived neurotrophic factor selectively prevent normally occurring neuronal death, while the targeted elimination of all three genes decreases neuronal numbers. As previous studies indicated that the lack of Neurotrophin-3 affects sensory ganglia already during gangliogenesis, the levels of this neurotrophin were increased during selected periods of chick development. We found that early, but not late, applications of Neurotrophin-3 lead to a marked decrease in neuronal numbers in peripheral sensory ganglia. This decrease is not seen with BDNF and does not selectively affect subtypes of dorsal root ganglion neurons. It is accompanied by, and might result from, a decrease in the number of proliferating neuroblasts in sensory ganglia of treated embryos.