Regular Article
NGF Binding to p75 Enhances the Sensitivity of Sensory and Sympathetic Neurons to NGF at Different Stages of Development

https://doi.org/10.1006/mcne.1997.0650Get rights and content

Abstract

To clarify the role of the common neurotrophin receptor p75 in modulating the survival response of sensory and sympathetic neurons to NGF at different stages of development, we compared the actions of wild-type NGF with a mutated NGF protein that binds normally to TrkA, the NGF receptor tyrosine kinase, but has greatly reduced binding to p75. At saturating concentrations, the NGF mutant promoted the survival of similar numbers of trigeminal sensory and sympathetic neurons as NGF. At subsaturating concentrations, the NGF mutant was less effective than wild-type NGF in promoting the survival of embryonic sensory neurons and postnatal sympathetic neurons but was equally effective as wild-type NGF in promoting the survival of embryonic sympathetic neurons. Whereas the levels oftrkAand p75 were similar in embryonic sensory neurons and postnatal sympathetic neurons, the level of p75 was significantly lower than that oftrkAin embryonic sympathetic neurons. These results indicate that binding of NGF to p75 enhances the sensitivity of NGF-dependent neurons to NGF at stages in their development when the levels of p75 and TrkA are similar

References (57)

  • A. Shih et al.

    Mutagenesis identifies amino-terminal residues of nerve growth factor necessary for trk receptor binding and biological activity

    J. Biol. Chem.

    (1994)
  • W.D. Snider

    Functions of the neurotrophins during nervous system development: What the knockouts are teaching us

    Cell

    (1994)
  • A. Sutter et al.

    Nerve growth factor receptors. Characterization of two distinct classes of binding sites on chick embryo sensory ganglia

    J. Biol. Chem.

    (1979)
  • J.M. Verdi et al.

    Neurotrophins regulate sequential changes in neurotrophin receptor expression by sympathetic neuroblasts

    Neuron

    (1994)
  • J.M. Verdi et al.

    p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells

    Neuron

    (1994)
  • D.E. Wolf et al.

    Interaction with TrkA immobilizes gp75 in the high affinity nerve growth factor receptor complex

    J. Biol. Chem.

    (1995)
  • E.S. Anton et al.

    Nerve growth factor and its low-affinity receptor promote Schwann cell migration

    Proc. Natl. Acad. Sci. USA

    (1994)
  • D.S. Battleman et al.

    HSV-1 vector-mediated gene transfer of the human nerve growth factor receptor p75hNGFR defines high-affinity NGF binding

    J. Neurosci.

    (1993)
  • M. Benedetti et al.

    Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness

    Proc. Natl. Acad. Sci. USA

    (1993)
  • M.M. Berg et al.

    The low-affinity p75 nerve growth factor (NGF) receptor mediates NGF-induced tyrosine phosphorylation

    Proc. Natl. Acad. Sci. USA

    (1991)
  • M. Bothwell

    Functional interactions of neurotrophins and neurotrophin receptors

    Annu. Rev. Neurosci.

    (1995)
  • M. Canossa et al.

    p75NGFR and TrkA receptors collaborate to rapidly activate a p75NGFR-associated protein kinase

    EMBO J.

    (1996)
  • B.D. Carter et al.

    Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75

    Science

    (1996)
  • P. Casaccia-Bonnefil et al.

    Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75

    Nature

    (1996)
  • D.O. Clary et al.

    An alternatively spliced form of the nerve growth factor receptor TrkA confers an enhanced response to neurotrophin-3

    Proc. Natl. Acad. Sci. USA

    (1994)
  • A.M. Davies

    Role of neurotrophins in the developing nervous system

    J. Neurobiol.

    (1994)
  • A.M. Davies et al.

    Relation of target encounter and neuronal death to nerve growth factor responsiveness in the developing mouse trigeminal ganglion

    J. Comp. Neurol.

    (1984)
  • R.T. Dobrowsky et al.

    Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor

    Science

    (1994)
  • Cited by (37)

    • Mechanisms of disease: Role of neurotrophins in diabetes and diabetic neuropathy

      2014, Handbook of Clinical Neurology
      Citation Excerpt :

      The Trks exhibit some selectivity in their preference for neurotrophin binding – NGF binds selectively to TrkA, BDNF and NT-4/5 to TrkB, and NT-3 preferentially to TrkC, but can also activate TrkB and TrkA at higher concentrations (Lu et al., 2005; Reichardt, 2006). Both p75NTR and Trk receptors can function individually, but they are often coexpressed where they form complexes (i.e., p75NTR and Trks) that have a higher affinity for the neurotrophin than the receptors individually, allowing the neurotrophin to act at lower concentrations and potentiating the signaling response (Hempstead et al., 1991; Horton et al., 1997; Bibel et al., 1999). NT-3/TrkA interactions may be the exception to this rule as the presence of p75 results in reduced activation of TrkA by NT-3 (Mischel et al., 2001).

    • Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System

      2013, Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS
    • Therapeutic Potential of Neurotrophic Factors

      2005, From NEUROSCIENCE To NEUROLOGY
    • Therapeutic Potential of Neurotrophic Factors

      2004, From Neuroscience to Neurology: Neuroscience, Molecular Medicine, and the Therapeutic Transformation of Neurology
    View all citing articles on Scopus
    1

    The first two authors contributed equally to this work.

    View full text