G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 31; pp. 12925 - 12930
• Main Authors: Luo, Rong, Jeong, Sung-Jin, Jin, Zhaohui, Strokes, Natalie, Li, Shihong, Piao, Xianhua
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.08.2011; National Acad Sciences
• Subjects: abnormal development; adhesion; Animals; basement membrane; Basement Membrane - embryology; Basement Membrane - metabolism; Basement Membrane - ultrastructure; Biological Sciences; biotinylation; Brain; Brain - embryology; Brain - metabolism; Cell lines; Cell Movement - drug effects; Cells, Cultured; cerebral cortex; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Cobblestone Lissencephaly - genetics; Cobblestone Lissencephaly - metabolism; collagen; Collagen Type III - genetics; Collagen Type III - metabolism; Collagens; G-protein coupled receptors; Gene expression regulation; genes; Glycoproteins; GTP-Binding Protein alpha Subunits, G12-G13 - metabolism; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Laminates; Ligands; Membranes; Mice; Mice, Knockout; Microscopy, Immunoelectron; mutants; Mutation; Neuroglia; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; NIH 3T3 Cells; phenotype; Protein Binding; proteomics; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Recombinant Proteins - pharmacology; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Rodents
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1104821108

GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα₁₂/₁₃ family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.