| First Author | Tsui CC | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 38 | Pages | 13233-43 |
| PubMed ID | 26400951 | Mgi Jnum | J:226474 |
| Mgi Id | MGI:5697574 | Doi | 10.1523/JNEUROSCI.2935-14.2015 |
| Citation | Tsui CC, et al. (2015) Lipid Rafts Are Physiologic Membrane Microdomains Necessary for the Morphogenic and Developmental Functions of Glial Cell Line-Derived Neurotrophic Factor In Vivo. J Neurosci 35(38):13233-43 |
| abstractText | 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 alpha1 (GFRalpha1) and the receptor tyrosine kinase Ret. Although Ret signal transduction in vitro is augmented by translocation into lipid rafts via GFRalpha1, the existence and importance of lipid rafts in GDNF-Ret signaling under physiologic conditions is unresolved. A knock-in mouse was produced that replaced GFRalpha1 with GFRalpha1-TM, which contains a transmembrane (TM) domain instead of the GPI anchor. GFRalpha1-TM still binds GDNF and promotes Ret activation but does not translocate into rafts. In Gfralpha1(TM/TM) mice, GFRalpha1-TM is expressed, trafficked, and processed at levels identical to GFRalpha1. Although Gfralpha1(+/TM) mice are viable, Gfralpha1(TM/TM) mice display bilateral renal agenesis, lack enteric neurons in the intestines, and have motor axon guidance deficits, similar to Gfralpha1(-/-) mice. Therefore, the recruitment of Ret into lipid rafts by GFRalpha1 is required for the physiologic functions of GDNF in vertebrates. SIGNIFICANCE STATEMENT: Membrane microdomains known as lipid rafts have been proposed to be unique subdomains in the plasma membrane that are critical for the signaling functions of multiple receptor complexes. Their existence and physiologic relevance has been debated. Based on in vitro studies, lipid rafts have been reported to be necessary for the function of the Glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors. The receptor for GDNF comprises the lipid raft-resident, glycerophosphatidylinositol-anchored receptor GDNF family receptor alpha1 (GFRalpha1) and the receptor tyrosine kinase Ret. Here we demonstrate, using a knock-in mouse model in which GFRalpha1 is no longer located in lipid rafts, that the developmental functions of GDNF in the periphery require the translocation of the GDNF receptor complex into lipid rafts. |
