Attenuation of a caspase-3 dependent cell death in NT4-and p75-deficient embryonic sensory neurons

Neuronal survival during the developmental period of naturally occurring ce ll death is mediated through a successful competition for limiting concentr ations of neurotrophic factors, and the deprived neurons will die. New resu lts show that induced death through the p75 neurotrophin receptor (p75(NTR) ), a member of the p55TNF/Fas family of cell death receptors, may also infl uence survival during development. We find that eliminating p75(NTR) or neu rotrophin 4 (NT4) in mice leads to a marked attenuation of apoptosis during the programmed cell death period of the trigeminal ganglion neurons, sugge sting that NT4 can induce the death of these neurons through the p75(NTR). These in vivo findings were reproduced in primary cell cultures, where NT4 was found to induce death in a p75(NTR)-dependent pathway. Analysis of p75 deficient and wild-type cells revealed two separate cell death pathways, a p75(NTR)- and caspase-3-independent pathway activated by trophic factor dep rivation, and a p75(NTR)- and caspase-3-dependent pathway initiated by NT4. Crossing in the NT4 null alleles in brain-derived neurotrophic factor (BDN F) null mutant mice led to a rescue of a large proportion of BDNF-dependent neurons from excessive cell death, indicating that trophic factor deprivat ion is not sufficient for the death of many neurons and that additional dea th inducing signals might be required. Our results suggest that NT4 competi tively signals survival and death of sensory neurons through trkB and p75(N TR), respectively.