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: GFR alpha -1 for GDNF, GFR alpha -2 for neurturin, GFR alpha -3 for enovin/artemin, and (chicken) GFR alpha -4 for persephin. Subsequent signaling occurs through activation of a common transmembrane tyrosine kinase, cRET. GFR alpha -4, the coreceptor for persephin, was previously identified in chicken only. We describe the cloning and characterization of a mammalian persephin receptor GFR alpha -4 The novel GFR alpha receptor is substantially different in sequence from all known GFR alphas, including chicken GFR alpha -4, and lacks the first cysteine-rich domain present in all previously characterized GFR alphas. At least two different GFR alpha -4 splice variants exist in rat tissues, differing at their respective COOH termini. GFR alpha -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 GFR alpha -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 GFR alpha -4 receptor, but no cRET activation could be demonstrated. Although the newly characterized mammalian GFR alpha -4 receptor is structurally divergent from previously characterized GFR alpha 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.