The Experts below are selected from a list of 19185 Experts worldwide ranked by ideXlab platform

Hans Thoenen - One of the best experts on this subject based on the ideXlab platform.

  • neurotrophin evoked rapid excitation through trkb receptors
    Nature, 1999
    Co-Authors: Karl W Kafitz, Hans Thoenen, Christine R Rose, Arthur Konnerth
    Abstract:

    Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons1,2,3. They are also essential for modulating activity-dependent neuronal plasticity4,5,6,7. Here we show that neurotrophins elicit action potentials in central neurons. Even at low concentrations, brain-derived neurotrophic factor (BDNF) excited neurons in the hippocampus, cortex and cerebellum. We found that BDNF and Neurotrophin-4/5 depolarized neurons just as rapidly as the neurotransmitter glutamate, even at a more than thousand-fold lower concentration. Neurotrophin-3 produced much smaller responses, and nerve growth factor was ineffective. The neurotrophin-induced depolarization resulted from the activation of a sodium ion conductance which was reversibly blocked by K-252a, a protein kinase blocker which prefers tyrosine kinase Trk receptors8. Our results demonstrate a very rapid excitatory action of neurotrophins, placing them among the most potent endogenous neuro-excitants in the mammalian central nervous system described so far.

  • neurotrophin 6 is a new member of the nerve growth factor family
    Nature, 1994
    Co-Authors: Rudolf Gotz, Franz Raulf, Manfred Schartl, Reinhard W. Köster, Friedrich Lottspeich, Christoph Winkler, Hans Thoenen
    Abstract:

    DURING vertebrate development, many neurons depend for survival and differentiation on their target cells1–3. The best documented mediator of such a retrograde trophic action is the neurotrophin nerve growth factor (NGF)1. NGF and the other known members of the neurotrophin family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and Neurotrophin-4/5 (NT-4/5) are conserved as distinct genes over large evolutionary distances4–6. Here we report the cloning of neurotrophin-6 (NT-6), a new mem-ber of this family from the teleost fish Xiphophorus. NT-6 dis-tinguishes itself from the other known neurotrophins in that it is not found as a soluble protein in the medium of producing cells. The addition of heparin (but not chondroitin) effects the release of NT-6 from cell surface and extracellular matrix molecules. Recombinant purified NT-6 has a spectrum of actions similar to NGF on chick sympathetic and sensory neurons, albeit with a lower potency. NT-6 is expressed in the embryonic valvulla cerebelli; expression persists in some adult tissues. The interaction of NT-6 with heparin-binding molecules may modulate its action in the nervous system.

  • Brain-derived neurotrophic factor and Neurotrophin-4 increase neurotrophin-3 expression in the rat hippocampus.
    International Journal of Developmental Neuroscience, 1994
    Co-Authors: Dan Lindholm, Hans Thoenen, Maria Da Penha Berzaghi, Jonathan D. Cooper, Eero Castrén
    Abstract:

    Hippocampal levels of mRNA encoding nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are rapidly induced by enhanced neuronal activity following seizures and glutamate or muscarinic receptor activation. However, the levels of neurotrophin-3 (NT-3) mRNA acutely decrease after limbic seizures suggesting that a different mode of regulation may exist for these neurotrophins. Here we show that BDNF and Neurotrophin-4 (NT-4), but not NT-3 itself, up-regulate NT-3 mRNA in cultured hippocampal neurons. In the rat hippocampus, the muscarinic receptor agonist, pilocarpine increased BDNF mRNA levels rapidly and those of NT-3 with a delay of several hours. Injection of BDNF into neonatal rats elevated NT-3 mRNA in the hippocampus which demonstrates that BDNF is able to enhance NT-3 expression in vivo. The regulation of NT-3 by BDNF and NT-4 enlargens the neurotrophic spectrum of these neurotrophins to include neuron populations responsive primarily to NT-3.

  • the changing scene of neurotrophic factors
    Trends in Neurosciences, 1991
    Co-Authors: Hans Thoenen
    Abstract:

    Abstract The purification of brain-derived neurotrophic factor (BDNF), the elucidation of its primary structure, and the subsequent identification of neurotrophin-3 (NT-3) ended the monopoly of NGF as the only well-characterized, target-derived neurotrophic molecule. NGF, BDNF and NT-3 are members of a gene family called neurotrophins. They have strictly conserved domains that determine their basic structure. However, they also have distinctly variable domains that determine their different neuronal specificity mediated by different high affinity receptors, and that share a common low affinity subunit. These similarities and dissimilarities between the members of the neurotrophin gene family are also reflected by their regional distribution, cellular localization and developmental regulation. In this article the neurotrophins are compared with ciliary neurotrophic factor (CNTF), which is a representative of the category of neurotrophic molecules that, according to their regional distribution, developmental expression and cellular localization, do not fulfil the criteria of a target-derived neurotrophic molecule. The physiological and pathophysiological functions of neurotrophins and CNTF are discussed in the context of their potential use for the treatment of traumatic and degenerative diseases of the peripheral and central nervous systems.

Eric M Shooter - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2004
    Co-Authors: Junji Yamauchi, Jonah R Chan, Eric M Shooter
    Abstract:

    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.

  • 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, 2003
    Co-Authors: Junji Yamauchi, Jonah R Chan, Eric M Shooter
    Abstract:

    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.

  • the neurotrophin receptor p75ntr as a positive modulator of myelination
    Science, 2002
    Co-Authors: Jose Miguel Cosgaya, Jonah R Chan, Eric M Shooter
    Abstract:

    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.

  • p75 reduces TrkB tyrosine autophosphorylation in response to brain-derived neurotrophic factor and neurotrophin 4/5.
    Journal of Biological Chemistry, 2000
    Co-Authors: Jouni Vesa, Alex Krüttgen, Eric M Shooter
    Abstract:

    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.

  • Neurotrophins induce release of neurotrophins by the regulated secretory pathway
    Proceedings of the National Academy of Sciences of the United States of America, 1998
    Co-Authors: Alex Krüttgen, J. Carsten Möller, John Victor Heymach, Eric M Shooter
    Abstract:

    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.

Kimberley A Mcallister - One of the best experts on this subject based on the ideXlab platform.

  • neurotrophin regulation of cortical dendritic growth requires activity
    Neuron, 1996
    Co-Authors: Kimberley A Mcallister, Lawrence C Katz, Donald C Lo
    Abstract:

    Abstract Neurotrophins have been proposed to mediate several forms of activity-dependent competition in the central nervous system. A key element of such hypotheses is that neurotrophins act preferentially on active neurons; however, little direct evidence supports this postulate. We therefore examined, in ferret cortical brain slices, the interactions between activity and neurotrophins in regulating dendritic growth of layer 4 pyramidal neurons. Inhibition of spontaneous electrical activity, synaptic transmission, or L-type calcium channels each prevented the otherwise dramatic increase in dendritic arborizations elicited by brain-derived neurotrophic factor. In developing cortex, this requirement for conjoint neurotrophin signaling and activity provides a mechanism for selectively enhancing the growth and connectivity of active neurons.

  • neurotrophins regulate dendritic growth in developing visual cortex
    Neuron, 1995
    Co-Authors: Kimberley A Mcallister, Donald C Lo, Lawrence C Katz
    Abstract:

    Abstract Although dendritic growth and differentiation are critical for the proper development and function of neocortex, the molecular signals that regulate these processes are largely unknown. The potential role of neurotrophins was tested by treating slices of developing visual cortex with NGF, BDNF, NT-3, or NT-4 and by subsequently visualizing the dendrites of pyramidal neurons using particle-mediated gene transfer. Specific neurotrophins increased the lenght and complexity of dendrites of defined cell populations. Basal dendrites of neurons in each cortical layer responded most strongly to a single neurotrophin: neurons in layer 4 to BDNF and neurons in layers 5 and 6 to NT-4. In contrast, apical dendrites responded to a range of neurotrophins. On both apical and basal dendrites, the effects of the TrkB receptor ligands, BDNF and NT-4, were distinct. The spectrum of neurotrophic actions and the laminar specificity of these actions implicate endogenous neurotrophins as regulatory signals in the development of specific dendritic patterns in mammalian neocortex.

Louis F Reichardt - One of the best experts on this subject based on the ideXlab platform.

  • characterization of neurotrophin and trk receptor functions in developing sensory ganglia direct nt 3 activation of trkb neurons in vivo
    Neuron, 1998
    Co-Authors: Isabel Farinas, George A Wilkinson, Carey Backus, Louis F Reichardt, Ardem Patapoutian
    Abstract:

    Spinal sensory ganglia have been shown to contain neuronal subpopulations with different functions and neurotrophin dependencies. Neurotrophins act, in large part, through Trk receptor tyrosine kinases: nerve growth factor (NGF) via TrkA, brain-derived neurotrophic factor (BDNF) and Neurotrophin-4/5 (NT-4/5) via TrkB, and neurotrophin-3 (NT-3) via TrkC. In the present paper, we use antibodies to TrkA, TrkB, and TrkC to characterize their expression patterns and to determine which subpopulations of cells are lost in mice lacking individual neurotrophins or Trk receptors. Despite previous reports of Trk receptor mRNAs in neural crest cells, we detect Trk receptor proteins only in neurons and not in neural crest cells or neuronal precursors. Comparisons of neonatal mice deficient in NT-3 or its cognate receptor TrkC have shown that there is a much greater deficiency in spinal sensory neurons in the former, suggesting that NT-3 may activate receptors in addition to TrkC. Using the same antibodies, we show that, during the major period of neurogenesis, NT-3 is required to maintain neurons that express TrkB in addition to those that express TrkC but is not essential for neurons expressing TrkA. Results also indicate that survival of cells expressing both receptors can be maintained by activation of either one alone. NT-3 can thus activate more than one Trk receptor in vivo, which when coexpressed are functionally redundant.

  • severe sensory and sympathetic deficits in mice lacking neurotrophin 3
    Nature, 1994
    Co-Authors: Isabel Farinas, Carey Backus, Kevin R. Jones, Xiaoyun Wang, Louis F Reichardt
    Abstract:

    DURING development, neurotrophins help shape the nervous system by regulating neuronal survival and differentiation. Neurotrophin-3 (refs 1–5) is the most abundant neurotrophin during early development6. Neurons responsive to neurotrophin-3 in vitro include primary sensory, sympathetic1–4 motor7, enteric1, locus coeruleus8, hippocampal and cerebellar neurons (ref. 9 for example). Here we report that mice lacking neurotrophin-3 have severe deficits in sensory and sympathetic populations. These mice lack muscle spindles and show abnormal limb positions. In contrast, motor neurons, the enteric nervous system, and the major anatomical regions of the central nervous system seem to develop normally. Comparisons with mutants deficient in other neurotrophins10–12 or their receptors13–15indicate that some neurons require more than one neurotrophin during embryogenesis and suggest that neurotrophin-3 functions by binding receptors in addition to its primary receptor trkC (ref. 16). In particular, neurotrophin-3 is essential for survival of sympathetic and sensory neurons that later become dependent on nerve growth factor or brain-derived neurotrophic factor.

Kalipada Pahan - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2013
    Co-Authors: Grant T Corbett, Kalipada Pahan
    Abstract:

    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.

  • sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase c pkc mediated activation of camp response element binding protein creb
    2013
    Co-Authors: Grant T Corbett, Kalipada Pahan
    Abstract:

    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