Lipid rafts are physiologic membrane microdomains necessary for the morphogenic and developmental functions of glial cell line-derived neurotrophic factor in vivo

Abstract

Glial cell line-derived neurotrophic factor (GDNF) promotes PNS development and kidney morphogenesis via a receptor complex consisting of the glycerophosphatidylinositol (GPI)-anchored, ligand binding receptor GDNF family receptor α1 (GFRα1) and the receptor tyrosine kinase Ret. Although Ret signal transduction in vitro is augmented by translocation into lipid rafts via GFRα1, the existence and importance of lipid rafts in GDNF–Ret signaling under physiologic conditions is unresolved. A knock-in mouse was produced that replaced GFRα1 with GFRα1–TM, which contains a transmembrane (TM) domain instead of the GPI anchor. GFRα1–TM still binds GDNF and promotes Ret activation but does not translocate into rafts. In Gfrα1™/™ mice, GFRα1–TM is expressed, trafficked, and processed at levels identical to GFRα1. Although Gfrα1+/™ mice are viable, Gfrα1™/™ mice display bilateral renal agenesis, lack enteric neurons in the intestines, and have motor axon guidance deficits, similar to Gfrα1-/-mice. Therefore, the recruitment of Ret into lipid rafts by GFRα1 is required for the physiologic functions of GDNF in vertebrates.