Expression and regulation of GFRα3, a glial cell line-derived neurotrophic factor family receptor

We report the identification of an additional member of the glial cell line-derived neurotrophic factor (GDNF) family receptor, termed GFR alpha 3, that is homologous to the previously identified GDNF and neurturin ligand binding receptors GFR alpha 1 and GFR alpha 2. GFR alpha 3 is 32 % and 37 % identical to GFR alpha 1 and GFR alpha 2, respectively, RNase protection assays show that whereas gfr alpha 1 and gfr alpha 2 are abundant in both developing and adult brain, gfr alpha 3 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 gfr alpha 2 and gfr alpha 3 are expressed in different subpopulations of neurons, whereas gfr alpha 1 is coexpressed in some gfr alpha 2 and gfr alpha 3-positive neurons, We find that the gfr alpha 1 population of trigeminal neurons is absent in GDNF null mutant mice, suggesting that GDNF signals in vivo by interacting with GFR alpha 1. 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 gfr alpha 3 implies distinct functions in the developing and adult mouse from that of GFR alpha 1 and GFR alpha 2.