P75-DEFICIENT EMBRYONIC DORSAL-ROOT SENSORY AND NEONATAL SYMPATHETIC NEURONS DISPLAY A DECREASED SENSITIVITY TO NGF

To understand the role of low-affinity neurotrophin receptor p75 in ne ural development, we previously generated mice carrying a null mutatio n in the p75 locus (Lee, K.F., Li, E., Huber, L.J., Landis, S.C., Shar pe, A.H., Chao, M.V. and Jaenisch, R. (1992) Cell 69, 737-749). To elu cidate the mechanisms leading to deficits in the peripheral nervous sy stem in p75 mutant mice, we have employed dissociated cultures to exam ine the responses of p75-deficient dorsal root ganglion (DRG) and supe rior cervical ganglion (SCG) neurons to different neurotrophins. We fo und that p75-deficient DRG and SCG neurons displayed a 2- to 3-fold de creased sensitivity to NGF at embryonic day 15 (E15) and postnatal day 3 (P3), respectively, ages that coincide with the peak of naturally o ccurring cell death. Furthermore, while p75-deficient E15 DRG neurons did not change their response specificity to BDNF, NT-3, and NT-4/5, P 3 SCG neurons became moreresponsive to NT-3 at higher concentrations ( nanomolar ranges). These resultsmay help explain the deficits in the p eripheral nervous system in p75 mutant mice and provide evidence that p75 can modulate neurotrophin sensitivity in some neurons.