To understand the role of low-affinity neurotrophin receptor p75 in neural development, we previously generated mice carrying a null mutation in the p75 locus (Lee, K. F., Li, E., Huber, L. J., Landis, S. C., Sharpe, A. H., Chao, M. V. and Jaenisch, R. (1992) Cell 69, 737-749). To elucidate the mechanisms leading to deficits in the peripheral nervous system in p75 mutant mice, we have employed dissociated cultures to examine the responses of p75-deficient dorsal root ganglion (DRG) and superior cervical ganglion (SCG) neurons to different neurotrophins. We found that p75-deficient DRG and SCG neurons displayed a 2- to 3-fold decreased sensitivity to NGF at embryonic day 15 (E15) and postnatal day 3 (P3), respectively, ages that coincide with the peak of naturally occurring cell death. Furthermore, while p75-deficient E15 DRG neurons did not change their response specificity to BDNF, NT-3, and NT-4/5, P3 SCG neurons became more responsive to NT-3 at higher concentrations (nanomolar ranges). These results may help explain the deficits in the peripheral nervous system in p75 mutant mice and provide evidence that p75 can modulate neurotrophin sensitivity in some neurons.