Is GAS1 a co-receptor for the GDNF family of ligands?

Glial-cell-line-derived neurotrophic factor (GDNF) is a survival and maintenance factor for dopamine-containing neurons and motoneurons. GDNF belongs to a family of structurally related factors that includes neurturin (NRTN), artemin (ARTN) and persephin (PSPN). An initial step in the activation of signaling via the GDNF family of ligands (GFLs) is their binding to their cognate co-receptor GFR alpha. GAS1, an apparently unrelated protein, exhibits homology to GFR alpha and thus we hypothesize that GAS1 can serve as an alternative receptor for GFLs. The functional similarity between GFR alpha and GAS1 extends to their role in embryogenesis, differentiation and glia maintenance, and is substantiated by overlap in their expression profile, subcellular localization and structural details. We propose that the relative expression and localization of the two remote receptors, GFR alpha and GAS1, on the membranes of neuronal and glial cells determines whether these cells survive or undergo apoptotic death.