Abstract
We report the identification of an additional member of the glial cell line-derived neurotrophic factor (GDNF) family receptor, termed GFRalpha3, that is homologous to the previously identified GDNF and neurturin ligand binding receptors GFRalpha1 and GFRalpha2. GFRalpha3 is 32% and 37% identical to GFRalpha1 and GFRalpha2, respectively. RNase protection assays show that whereas gfralpha1 and gfralpha2 are abundant in both developing and adult brain, gfralpha3 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 gfralpha2 and gfralpha3 are expressed in different subpopulations of neurons, whereas gfralpha1 is coexpressed in some gfralpha2 and gfralpha3-positive neurons. We find that the gfralpha1 population of trigeminal neurons is absent in GDNF null mutant mice, suggesting that GDNF signals in vivo by interacting with GFRalpha1. 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 gfralpha3 implies distinct functions in the developing and adult mouse from that of GFRalpha1 and GFRalpha2.
Highlights
In the vertebrate nervous system, the survival of many neuronal populations is controlled by neurotrophic factors often produced by the targets of innervation
GFR␣3 was identified by a BLAST search in the dbEST sequence databank by using the protein sequence of GDNF family receptor ␣1 (GFR␣1) as template [43]
The result that GFR␣3 displays a lower homology to GFR␣1 and GFR␣2 than GFR␣1 and GFR␣2 does suggests that GFR␣3 is a more distant member in this family of receptors
Summary
In the vertebrate nervous system, the survival of many neuronal populations is controlled by neurotrophic factors often produced by the targets of innervation. A family of neurotrophic factors has been discovered, including the structurally related ligands glial cell linederived neurotrophic factor (GDNF) and neurturin (NTN) [26, 27]. They are distant members to the transforming growth factor  family. Less is known about the functions of NTN In culture, this factor has been shown to stimulate the survival of peripheral sensory and sympathetic neurons [27]. When present at low concentrations GDNF and NTN can display a preference for GFR␣1 and GFR␣2, respectively [39, 47]
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