Neurturin (NTN) is a neuronal survival factor that activates the Ret tyrosine kinase in the presence of a GPI-linked coreceptor (either GFRα1 or GFRα2). Neurturin-deficient (NTN(-/-)) mice generated by homologous recombination are viable and fertile but have defects in the enteric nervous system, including reduced myenteric plexus innervation density and reduced gastrointestinal motility. Parasympathetic innervation of the lacrimal and submandibular salivary gland is dramatically reduced in NTN(-/-) mice, indicating that Neurturin is a neurotrophic factor for parasympathetic neurons. GFRα2-expressing cells in the trigeminal and dorsal root ganglia are also depleted in NTN(-/-) mice. The loss of GFRα2-expressing neurons, in conjunction with earlier studies, provides strong support for GFRα2/Ret receptor complexes as the critical mediators of NTN function in vivo.