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

We have investigated whether the transcription factor NF-kappa B plays a ro le in regulating neuronal survival by manipulating NF-kappa B activation in the nerve growth factor (NGF)-dependent sensory neurons of the embryonic m ouse trigeminal ganglion. Overexpression of either the p65 or the p50 NF-ka ppa B subunits resulted in NF-kappa B activation and promoted in vitro surv ival as effectively as NGF. Expression of a superrepressor I kappa B-alpha protein prevented NF-kappa B activation in p65/p50-overexpressing neurons a nd caused the neurons to die as rapidly as NGF-deprived neurons. NGF treatm ent also activated NF-kappa B, and preventing this activation with superrep ressor I kappa B-alpha reduced the NGF survival response. Antibodies that b lock binding of NGF to the p75 receptor prevented NGF-induced NF-kappa B ac tivation and reduced the NGF survival response to the same extent as superr epressor I kappa B-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 sensor y neurons, p68-deficient sensory neurons showed a normal survival response to BDNF. These results reveal a role for NF-kappa B in regulating neuronal survival during embryonic development and suggest that in addition to the w ell-established Trk receptor tyrosine kinase signaling cascade, NGF enhance s neuronal survival by signaling via a p75-mediated pathway.