GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF)¹ is a potent survival factor for dopaminergic neurons and motor neurons in culture^1,2. It also protects these neurons from degeneration in vitro^3–9, and improves symptoms like Parkinson's disease induced pharmacologically in rodents¹⁰ and monkeys¹¹. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons¹. GDNF-null mice, regardless of their targeted mutation, display complete renal agenesis owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.