The survival of neurons in the developing isthmo-optic nucleus (ION) is believed to depend on the retrograde transport of trophic molecules from the target, the contralateral retina. We now show that ION neurons transport nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) retrogradely and that BDNF and NT-3 support the survival of ION neurons in vivo and promote neurite outgrowth in vitro. Surprisingly, NGF enhanced normal developmental cell death in vivo in a dose-dependent way. These findings show that increased levels of NGF can have adverse effects on differentiated neurons. The negative effect of NGF could be mimicked by intraocular injection of antibodies that block binding of neurotrophins to the 75 kd neurotrophin receptor (p75). These data implicate a role for the p75 receptor in NGF's neurotoxicity and indicate that this receptor is involved in the mechanism by which ION neurons respond to BDNF and NT-3 in the target.