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

Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12925-30. doi: 10.1073/pnas.1104821108. Epub 2011 Jul 18.


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 Gα(12/13) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / embryology
  • Basement Membrane / metabolism*
  • Basement Membrane / ultrastructure
  • Brain / embryology
  • Brain / metabolism
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism*
  • Cobblestone Lissencephaly / genetics
  • Cobblestone Lissencephaly / metabolism
  • Collagen Type III / genetics
  • Collagen Type III / metabolism*
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • NIH 3T3 Cells
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Protein Binding
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Proteins / pharmacology
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism


  • Collagen Type III
  • GPR56 protein, mouse
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • GTP-Binding Protein alpha Subunits, G12-G13
  • rhoA GTP-Binding Protein