IDENTIFICATION AND CHARACTERIZATION OF GFR-ALPHA-3, A NOVEL CORECEPTOR BELONGING TO THE GLIAL-CELL LINE-DERIVED NEUROTROPHIC RECEPTOR FAMILY

A new family of neuronal survival factors comprised of glial cell line -derived neurotrophic factor (GDNF) and neurturin has recently been de scribed (Kotzbauer, P. T., Lampe, P. A., Heuckeroth, R. O., Golden, J. P., Creedon, D. J., Johnson, E. M., Jr., and Milbrandt, J. (1997) Nat ure 384, 467-470), These molecules, which are related to transforming growth factor-beta, are important in embryogenesis and in the survival of distinct neuronal populations, These molecules signal through a no vel receptor system that includes the Ret receptor tyrosine kinase, a ligand (i.e. GDNF or neurturin), and an accessory glycosyl-phosphatidy linositol-linked molecule that is responsible for high affinity bindin g of the ligand, Two accessory molecules denoted GDNF family receptor 1 and 2 (GFR alpha-1 and GFR alpha-2) have been described that functio n in GDNF and neurturin signaling complexes, We have identified a nove l co-receptor belonging to this family based on similarity to GFR alph a-1, which we have named GFR alpha-3. GFR alpha-3 displays 33% amino a cid identity with GFR alpha-1 and 36% identity with GFR alpha-2. Despi te the similarity of GFR alpha-3 to GFR alpha-1 and GFR alpha-2, it is unable to activate Ret in conjunction with GDNF, suggesting that ther e are likely additional undiscovered ligands and/or Ret-like receptors to be identified, GFR alpha-3 is anchored to the cell membrane by a p hosphatidylinositol-specific phospholipase C-resistant glycosyl-phosph atidylinositol linkage, GFR alpha-3 is highly expressed by embryonic d ay 11 but is not appreciably expressed in the adult mouse, In situ hyb ridization analyses demonstrate that GFR alpha-3 is located in dorsal root ganglia and the superior cervical sympathetic ganglion. Compariso n of the expression patterns of GFR alpha-3 and Ret suggests that thes e molecules could form a receptor pair and interact with GDNF family m embers to play unique roles in development.