We report the identification of an additional member of the glial cell line-derived neurotrophic factor (GDNF) family receptor, termed GFRα3, that is homologous to the previously identified GDNF and neurturin ligand binding receptors GFRα1 and GFRα2. GFRα3 is 32% and 37% identical to GFRα1 and GFRα2, respectively. RNase protection assays show that whereas gfrα1 and gfrα2 are abundant in both developing and adult brain, gfrα3 is exclusively expressed during development. All receptors are widely present in both the developing and adult peripheral nervous system and in peripheral organs. For instance, in situ hybridization shows that the developing liver, stomach, intestine, kidney, and sympathetic chain, which all contain ret-expressing cells, transcribe unique complementary and overlapping patterns of most or all of the GDNF family receptors and ligands. In sensory neurons of the trigeminal ganglion gfrα2 and gfrα3 are expressed in different subpopulations of neurons, whereas gfrα1 is coexpressed in some gfrα2 and gfrα3-positive neurons. We find that the gfrα1 population of trigeminal neurons is absent in GDNF null mutant mice, suggesting that GDNF signals in vivo by interacting with GFRα1. Thus, our results show that there are at least three members in the GDNF family of ligand binding receptors and that these receptors may be crucial in conferring ligand specificity in vivo. The unique complementary and overlapping expression of gfrα3 implies distinct functions in the developing and adult mouse from that of GFRα1 and GFRα2
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