GFRα3 is an orphan member of the GDNF/neurturin/persephin receptor family

GDNF, neurturin, and persephin are transforming growth factor beta-related neurotrophic factors known collectively as the GDNF family (GF). GDNF and neurturin signal through a multicomponent receptor complex containing a signaling component (the Ret receptor tyrosine kinase) and either of two glycosyl-phosphatidylinositol-linked binding components (GDNF family receptor alpha components 1 and 2, GFR alpha 1 or GFR alpha 2), whereas the receptor for persephin is unknown. Herein we describe a third member of the GF coreceptor family called GFR alpha 3 that is encoded by a gene located on human chromosome 5q31.2-32, GFR alpha 3 is not expressed in the central nervous system of the developing or adult animal but is highly expressed in several developing and adult sensory and sympathetic ganglia of the peripheral nervous system. GFR alpha 3 is also expressed at high levels in developing, but not adult, peripheral nerve. GFR alpha 3 is a glycoprotein that is glycosyl-phosphatidylinositol-linked to the cell surface like GFR alpha 1 and GFR alpha 2. Fibroblasts expressing Ret and GFR alpha 3 do not respond to any of the known members of the GDNF family, suggesting that GFR alpha 3 interacts with an unknown ligand or requires a different or additional signaling protein to function.