Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFRα2, a functional neurturin receptor

Glial cell line-derived neurotrophic factor (GDNF) and a related protein, neurturin (NTN), require a GPI-linked coreceptor, either GFR alpha 1 or GFR alpha 2, for signaling via the transmembrane Ret tyrosine kinase. We show that mice lacking functional GFR alpha 2 coreceptor (Gfra2(-/-)) are viable and fertile but have dry eyes and grow poorly after weaning, presumably due to malnutrition. While the sympathetic innervation appeared normal, the parasympathetic cholinergic innervation was almost absent in the lacrimal and salivary glands and severely reduced in the small bowel. Neurite outgrowth and trophic effects of NTN at low concentrations were lacking in Gfra2(-/-) trigeminal neurons in vitro, whereas responses to GDNF were similar between the genotypes. Thus, GFRa2 is a physiological NTN receptor, essential for the development of specific postganglionic parasympathetic neurons.