p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor

Mol Cell Neurosci. 1999 Jul;14(1):28-40. doi: 10.1006/mcne.1999.0770.

Abstract

We have investigated whether the transcription factor NF-kappaB plays a role in regulating neuronal survival by manipulating NF-kappaB activation in the nerve growth factor (NGF)-dependent sensory neurons of the embryonic mouse trigeminal ganglion. Overexpression of either the p65 or the p50 NF-kappaB subunits resulted in NF-kappaB activation and promoted in vitro survival as effectively as NGF. Expression of a superrepressor IkappaB-alpha protein prevented NF-kappaB activation in p65/p50-overexpressing neurons and caused the neurons to die as rapidly as NGF-deprived neurons. NGF treatment also activated NF-kappaB, and preventing this activation with superrepressor IkappaB-alpha reduced the NGF survival response. Antibodies that block binding of NGF to the p75 receptor prevented NGF-induced NF-kappaB activation and reduced the NGF survival response to the same extent as superrepressor IkappaB-alpha. Trigeminal neurons cultured from p65(-/-) embryos showed a reduced survival response to NGF compared with neurons from wild-type embryos and there was increased apoptosis of neurons in the trigeminal ganglia of p65(-/-) embryos in vivo. However, as with p75-deficient sensory neurons, p65-deficient sensory neurons showed a normal survival response to BDNF. These results reveal a role for NF-kappaB in regulating neuronal survival during embryonic development and suggest that in addition to the well-established Trk receptor tyrosine kinase signaling cascade, NGF enhances neuronal survival by signaling via a p75-mediated pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Apoptosis
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Cells, Cultured
  • Embryo, Mammalian
  • Mice
  • Mice, Knockout
  • NF-kappa B / deficiency
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nerve Growth Factors / pharmacology
  • Nerve Growth Factors / physiology*
  • Neurons, Afferent / cytology*
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / physiology*
  • Receptor, Nerve Growth Factor
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trigeminal Ganglion / cytology
  • Trigeminal Ganglion / physiology*

Substances

  • Antibodies
  • Brain-Derived Neurotrophic Factor
  • NF-kappa B
  • Nerve Growth Factors
  • Receptor, Nerve Growth Factor
  • Receptors, Nerve Growth Factor