GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney

Glial cell line-derived neurotrophic factor (GDNF) is a distant member of the TGF beta protein family that is essential for neuronal survival and renal morphogenesis. We show that mice who are deficient in the glycosyl-phosphatidyl inositol (GPI)-linked protein GFR alpha 1 (GDNFR alpha) display deficits in the kidneys, the enteric nervous system, and spinal motor and sensory neurons that are strikingly similar to those of the GDNF- and Ret-deficient mice. GFR alpha 1-deficient dopaminergic and nodose sensory ganglia neurons no longer respond to GDNF or to the structurally related protein neurturin (NTN) but can be rescued when exposed to GDNF or neurturin in the presence of soluble GFR alpha 1. in contrast, GFR alpha 1-deficient submandibular parasympathetic neurons retain normal response to these two factors. Taken together with the available genetic and biochemical data, these findings support the idea that GFR alpha 1 and the transmembrane tyrosine kinase net are both necessary receptor components for GDNF in the developing kidney and nervous system, and that GDNF and neurturin can mediate some of their activities through a second receptor.