Evolution of the GDNF family ligands and receptors

Four different ligand-receptor binding pairs of the GDNF (glial cell line-derived neurotrophic factor) family exist in mammals, and they all signal via the transmembrane RET receptor tyrosine kinase. In addition, GRAL (GDNF Receptor Alpha-Like) protein of unknown function and Gas1 (growth arrest specific 1) have GDNF family receptor (GFR)-like domains. Orthologs of the four GFR alpha receptors, GRAL and Gas1 are present in all vertebrate classes. in contrast, although bony fishes have orthologs of all four GDNF family ligands (GFLs), one of the ligands, neurturin, is absent in clawed frog and another, persephin, is absent in the chicken genome. Frog GFR alpha 2 has selectively evolved possibly to accommodate GDNF as a ligand. The key role of GDNF and its receptor GFR alpha 1 in enteric nervous system development is conserved from zebrafish to humans. The role of neurturin, signaling via GFR alpha 2, for parasympathetic neuron development is conserved between chicken and mice. The role of artemin and persephin that signal via GFR alpha 3 and GFR alpha 4, respectively, is unknown in non-mammals. The presence of RET- and GFR-like genes in insects suggests that a ProtoGFR and a Proto-RET arose early in the evolution of bilaterian animals, but when the ProtoGFL diverged from existing transforming growth factor (TGF beta)-like proteins remains unclear. The four GFLs and GFR alpha s were presumably generated by genome duplications at the origin of vertebrates. Loss of neurturin in frog and persephin in chicken suggests functional redundancy in early tetrapods. Functions of non-mammalian GFLs and prechordate RET and GFR-like proteins remain to be explored. Copyright (c) 2006 S. Karger AG, Basel.