GFRα-4 and the tyrosine kinase Ret form a functional receptor complex for persephin

Glial-cell-line-derived neurotrophic factor (GDNF) [1], neurturin [2] and persephin [3] are structurally related, secreted proteins that are widely expressed in the nervous system and other tissues [1–5] and promote the survival of a variety of neurons during development [1–12]. GDNF and neurturin signal through multicomponent receptors that consist of the Ret receptor tyrosine kinase and one of two structurally related glycosyl-phosphatidylinositol (GPI)-linked ligand-binding subunits: GFRα-1 is the preferred ligand-binding subunit for GDNF, and GFRα-2 is the preferred ligand-binding subunit for neurturin [13–21]. Two additional members of the GFRα family of GPI-linked proteins have recently been cloned: GFRα-3 [21–23] and GFRα-4 [24]. We have shown that persephin binds efficiently only to GFRα-4, and labelled persephin is effectively displaced from cells expressing GFRα-4 by persephin but not by GDNF or neurturin. Using microinjection to introduce expression plasmids into cultured neurons, we have also shown that coexpression of Ret with GFRα-4 confers a marked survival response to persephin but not to GDNF or neurturin. These results demonstrate that GFRα-4 is the ligand-binding subunit for persephin and that persephin, like GDNF and neurturin, also requires Ret for signalling.