GFRα1 Is an Essential Receptor Component for GDNF in the Developing Nervous System and Kidney

primary neuronal cultures, as well as in lesioned animal models, have provided evidence that GDNF is a survival factor for embryonic midbrain dopaminergic neurons shown to promote the survival of cultured dopaminergic Bute Medical Building, St. Andrews and motor, but not peripheral, neurons (Milbrandt et al., United Kingdom 1998). 6 Deltagen, Incorporated The essential physiological role of the GDNF/NTN/ San Carlos, California 94070 PSP protein family is illustrated by the phenotype of mice in whom the GDNF gene has been disrupted. These mice display deficits in primary sensory, sympathetic, Summary and motor neurons and also fail to develop metanephric kidneys, ureters, and most of the enteric nervous system Glial cell line–derived neurotrophic factor (GDNF) is a distant member of the TGF␤ protein family that is 1996). Consequently, although these mice are born, they essential for neuronal survival and renal morphogene-die shortly after birth, owing to an inability to consume sis. We show that mice who are deficient in the glyco-milk and to the lack of renal function. syl-phosphatidyl inositol (GPI)-linked protein GFR␣1 Despite the physiological and clinical significance of (GDNFR␣) display deficits in the kidneys, the enteric the GDNF protein family, the mechanism by which these nervous system, and spinal motor and sensory neu-growth factors transduce signals is not fully understood. rons that are strikingly similar to those of the GDNF-Biochemical and cell culture studies have suggested and Ret-deficient mice. GFR␣1-deficient dopaminer-that GDNF and NTN bind one of several glycosyl-phos-gic and nodose sensory ganglia neurons no longer phatidyl inositol (GPI)-linked proteins (designated GDNF respond to GDNF or to the structurally related protein family receptors GFR␣1–4) and that they also require neurturin (NTN) but can be rescued when exposed to the presence of the transmembrane tyrosine kinase Ret GDNF or neurturin in the presence of soluble GFR␣1. (data not shown). These GFR␣1 and the transmembrane tyrosine kinase Ret studies further revealed that GDNF and NTN facilitate are both necessary receptor components for GDNF in the formation of a physical complex between GFR␣ and the developing kidney and nervous system, and that Ret and lead to activation of the Ret tyrosine kinase GDNF and neurturin can mediate some of their activities through a second receptor. Taken together, the findings supported the proposal that cellular responses to the GDNF protein family are mediated through multicomponent receptor complexes Introduction composed of a shared signaling subunit, the orphan tyrosine kinase, Ret, and one of several …