MOTOR neurons require neurotrophic factor(s) for their survival during development and for maintenance of function in adulthood(1-3). In vivo studies have shown that motor neurons respond to a variety of molecules, including ciliary neurotrophic factor, members of the neurotrophin family, and the insulin growth factor IGF-1 (refs 3-13). Here we investigate the potential motor neuron neurotrophic effects of glial-cell-line-derived neurotrophic factor (GDNF), initially identified as a neurotrophic factor for substantia nigra dopaminergic neurons(14). We find that GDNF is retrogradely transported, in a receptor-mediated fashion, by spinal cord motor neurons in neonatal rats. Local application of GDNF to the transected nerve prevents the massive motor neuron cell death and atrophy that normally follows axotomy in the neonatal period. In adult rats, GDNF administered locally or systemically can markedly attenuate the lesion-induced decrease of choline acetyltransferase immunoreactivity in the facial nucleus. Our data indicate that GDNF has very profound neurotrophic effects in vivo on developing as well as on adult motor neurons, and is the most potent motor neuron trophic factor found so far.