p75-Mediated NF-κB Activation Enhances the Survival Response of Developing Sensory Neurons to Nerve Growth Factor

Abstract We have investigated whether the transcription factor NF-κB plays a role in regulating neuronal survival by manipulating NF-κB 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-κB subunits resulted in NF-κB activation and promoted in vitro survival as effectively as NGF. Expression of a superrepressor IκB-α protein prevented NF-κB activation in p65/p50-overexpressing neurons and caused the neurons to die as rapidly as NGF-deprived neurons. NGF treatment also activated NF-κB, and preventing this activation with superrepressor IκB-α reduced the NGF survival response. Antibodies that block binding of NGF to the p75 receptor prevented NGF-induced NF-κB activation and reduced the NGF survival response to the same extent as superrepressor IκB-α. 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-κB 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.