EXPRESSION AND REGULATION OF GFR-ALPHA-3, 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 a lpha 3, that is homologous to the previously identified GDNF and neurt urin 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, respective ly, RNase protection assays show that whereas gfr alpha 1 and gfr alph a 2 are abundant in both developing and adult brain, gfr alpha 3 is ex clusively expressed during development. All receptors are widely prese nt in both the developing and adult peripheral nervous system and in p eripheral organs, For instance, in situ hybridization shows that the d eveloping liver, stomach, intestine, kidney, and sympathetic chain, wh ich all contain ret-expressing cells, transcribe unique complementary and overlapping patterns of most or all of the GDNF family receptors a nd 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 trigemin al neurons is absent in GDNF null mutant mice, suggesting that GDNF si gnals 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 bin ding receptors and that these receptors may be crucial in conferring l igand specificity in vivo, The unique complementary and overlapping ex pression of gfr alpha 3 implies distinct functions in the developing a nd adult mouse from that of GFR alpha 1 and GFR alpha 2.