New insights into the control of neurotrophic growth factor receptor signaling: Implications for nervous system development and repair

Authors

  • Fernando C. Alsina,

    1. Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience Prof. Dr. E. De Robertis (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina
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  • Fernanda Ledda,

    1. Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience Prof. Dr. E. De Robertis (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina
    2. Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
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  • Gustavo Paratcha

    Corresponding author
    1. Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
    • Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience Prof. Dr. E. De Robertis (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina
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Address correspondence and reprint requests to Gustavo Paratcha. Division of Molecular and Cellular Neuroscience, Institute of Cellular Biology and Neuroscience Prof. Dr. E. De Robertis (IBCN)-CONICET, School of Medicine. University of Buenos Aires (UBA), Buenos Aires, Argentina. E-mails: gparatcha@fmed.uba.ar; gustavo.paratcha@ki.se

Abstract

Neurotrophic growth factors control neuronal development by activating specific receptor tyrosine kinase positive signaling pathways, such as Ras-MAPK and PI3K-Akt cascades. Once activated, neurotrophic factor receptors also trigger a cascade of molecular events, named negative receptor signaling, that restricts the intensity of the positive signals and modulates cellular behavior. Thus, to avoid signaling errors that ultimately could lead to aberrant neuronal physiology and disease, negative signaling mechanisms have evolved to ensure that suitable thresholds of neuronal stimulation are achieved and maintained during right periods of time. Recent findings have revealed that neurotrophic factor receptor signaling is tightly modulated through the coordinated action of many different protein regulators that limit or potentiate signal propagation in spatially and temporally controlled manners, acting at specific points after receptor engagement. In this review, we discuss progress in this field, highlighting the importance of these modulators in axonal growth, guidance, neural connectivity, and nervous system regeneration.

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