Mammalian GFRα-4, a divergent member of the GFRα family of coreceptors for glial cell line-derived neurotrophic factor family ligands, is a receptor for the neurotrophic factor persephin

Four members of the glial cell line-derived neurotrophic factor family have been identified (GDNF, neurturin, persephin, and enovin/artemin). They bind to a specific membrane-anchored GDNF family receptor as follows: GFRα-1 for GDNF, GFRα-2 for neurturin, GFRα-3 for enovin/artemin, and (chicken) GFRα-4 for persephin. Subsequent signaling occurs through activation of a common transmembrane tyrosine kinase, cRET. GFRα-4, the coreceptor for persephin, was previously identified in chicken only. We describe the cloning and characterization of a mammalian persephin receptor GFRα-4. The novel GFRα receptor is substantially different in sequence from all known GFRαs, including chicken GFRα-4, and lacks the first cysteine-rich domain present in all previously characterized GFRαs. At least two different GFRα-4 splice variants exist in rat tissues, differing at their respective COOH termini. GFRα-4 mRNA is expressed at low levels in different brain areas in the adult as well as in some peripheral tissues including testis and heart. Recombinant rat GFRα-4 variants were expressed in mammalian cells and shown to be at least partially secreted from the cells. Persephin binds specifically and with high affinity (K_D = 6 nM) to the rat GFRα-4 receptor, but no cRET activation could be demonstrated. Although the newly characterized mammalian GFRα-4 receptor is structurally divergent from previously characterized GFRα family members, we suggest that it is a mammalian orthologue of the chicken persephin receptor. This discovery will allow a more detailed investigation of the biological targets of persephin action and its potential involvement in diseases of the nervous system.