p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor.
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.
Hamanoue
M
M
School of Biomedical Sciences, University of St. Andrews, Biomedical Science Building, St. Andrews, KY16 9AJ, Scotland.
Middleton
G
G
Wyatt
S
S
Jaffray
E
E
Hay
R T
RT
Davies
A M
AM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D009475:Neurons, Afferent / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012668:Trigeminal Ganglion / Q000166:cytology / Q000502:physiology*
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D016328:NF-kappa B; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor