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

  • Neurotrophin regulated signalling pathways
    Philosophical Transactions of the Royal Society B, 2006
    Co-Authors: Louis F Reichardt
    Abstract:

    Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian Neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each Neurotrophin activates p75 Neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, Neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-g1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kB (NF-kB) and Jun kinase as well as other signalling pathways. Limiting quantities of Neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The Neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the Neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

  • 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, Carey Backus, Louis F Reichardt, George A Wilkinson, 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, Kevin R Jones, Carey Backus, 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.

Michael E Greenberg - One of the best experts on this subject based on the ideXlab platform.

  • creb a major mediator of neuronal Neurotrophin responses
    Neuron, 1997
    Co-Authors: Steven Finkbeiner, Sohail F Tavazoie, Anna Maloratsky, Kori M Jacobs, Kristen M Harris, Michael E Greenberg
    Abstract:

    Neurotrophins regulate neuronal survival, differentiation, and synaptic function. To understand how Neurotrophins elicit such diverse responses, we elucidated signaling pathways by which brain-derived neurotrophic factor (BDNF) activates gene expression in cultured neurons and hippocampal slices. We found, unexpectedly, that the transcription factor cyclic AMP response element-binding protein (CREB) is an important regulator of BDNF-induced gene expression. Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at least two signaling pathways: by a calcium/calmodulin-dependent kinase IV (CaMKIV)-regulated pathway that is activated by the release of intracellular calcium and by a Ras-dependent pathway. These findings reveal a previously unrecognized, CaMK-dependent mechanism by which Neurotrophins activate CREB and suggest that CREB plays a central role in mediating Neurotrophin responses in neurons.

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: Hans Thoenen, Karl W Kafitz, Arthur Konnerth, Christine R Rose
    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 release by Neurotrophins: Implications for activity-dependent neuronal plasticity
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: Marco Canossa, Oliver Griesbeck, Benedikt Berninger, Gabriele Campana, Roland Kolbeck, Hans Thoenen
    Abstract:

    Neurotrophins, secreted in an activity-dependent manner, are thought to be involved in the activity-dependent refinement of synaptic connections. Here we demonstrate that in hippocampal neurons and the rat pheochromocytoma cell line PC12 application of exogenous Neurotrophins induces secretion of Neurotrophins, an effect that is mediated by the activation of tyrosine kinase Neurotrophin receptors (Trks). Like activity-dependent secretion of Neurotrophins, Neurotrophin-induced Neurotrophin secretion requires mobilization of calcium from intracellular stores. Because Neurotrophins are likely to be released from both dendrites and axons, Neurotrophin-induced Neurotrophin release represents a potential positive feedback mechanism, contributing to the reinforcement and stabilization of synaptic connections.

  • Neurotrophin 6 is a new member of the nerve growth factor family
    Nature, 1994
    Co-Authors: Rudolf Gotz, Reinhard W Koster, Christoph Winkler, F Raulf, Friedrich Lottspeich, Manfred Schartl, 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.

  • 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.

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

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.