p75-mediated NF-kB 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 role in regulating neuronal survival by manipulating NF-kappa B 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-kappa B subunits resulted in NF-kappa B activation and promoted in vitro survival as effectively as NGF. Expression of a superrepressor I kappa B-alpha protein prevented NF-kappa B activation in p65/p50-overexpressing neurons and caused the neurons to die as rapidly as NGF-deprived neurons. NGF treatment also activated NF-kappa B, and preventing this activation with superrepressor I kappa B-alpha reduced the NGF survival response. Antibodies that block binding of NGF to the p75 receptor prevented NGF-induced NF-kappa B activation and reduced the NGF survival response to the same extent as superrepressor 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 sensory 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 well-established Trk receptor tyrosine kinase signaling cascade, NGF enhances neuronal survival by signaling via a p75-mediated pathway.