During development, neurons pass through a critical phase in which survival is dependent on neurotrophin support. In order to dissect the potential role of p75 NTR , the common neurotrophin receptor, in neurotrophin dependence, we expressed wild-type and mutant p75 NTR in cells that do not express endogenous p75 NTR or Trk family members (NIH3T3). Expression of wild-type p75 NTR created a state of neurotrophin dependence: cells could be rescued by nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3), but not by a mutant NGF that binds well to Trk A but poorly to p75 NTR . Similarly, expression of p75 NTR in human prostate cancer cells in culture rendered a metastatic tumor cell line (PC-3) sensitive to the availability of neurotrophins for survival. Moreover, expression of mutant p75 NTR 's in another neurotrophin-insensitive cell line (HEK293T) showed that a domain within the intracellular domain governs alternate responses to neurotrophins: the carboxy terminus of the intracellular domain of p75 NTR including the sixth alpha helix domain is necessary for rescue by BDNF, but not NGF. These results, when considered with previous studies of the timing of p75 NTR expression, support the hypothesis that p75NTR is a mediator of neurotrophin dependence during the critical phase of developmental cell death and during the progression of carcinogenesis in prostate cancer.