GPR56-regulated granule cell adhesion is essential for rostral cerebellar development.
Mutations in GPR56, an orphan G-protein-coupled receptor (GPCR), cause bilateral frontoparietal polymicrogyria (BFPP), a disorder characterized by mental retardation, seizures, motor developmental delay, and ataxia. BFPP patients have structural abnormalities of the cerebral cortex, cerebellum, and pons. To shed light on the function of GPR56 and the anatomical and behavioral defects underlying BFPP, we analyzed the cerebellum of mice lacking this GPCR. Gpr56(-/-) mice display a severe malformation of the rostral cerebellum that develops perinatally. Defects involve fusion of adjacent lobules, disrupted layering of neurons and glia, and fragmentation of the pial basement membrane. At the age of defect onset, GPR56 expression is restricted specifically to developing granule cells in the rostral cerebellum, suggesting that GPR56 regulates properties of these cells. Indeed, granule cells from the rostral region of perinatal Gpr56(-/-) cerebella show loss of adhesion to extracellular matrix molecules of the pial basement membrane. Interference RNA-mediated knockdown of GPR56 recapitulates the loss of adhesion seen in knock-outs, and reexpression of GPR56 rescues the adhesion defect in knock-out granule cells. Loss of GPR56 does not affect cell proliferation, migration, or neurite outgrowth. These studies establish a novel role for GPR56 in the adhesion of developing neurons to basal lamina molecules and suggest that this adhesion is critical for maintenance of the pia and proper cerebellar morphogenesis.
Koirala
Samir
S
F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Jin
Zhaohui
Z
Piao
Xianhua
X
Corfas
Gabriel
G
D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002531:Cerebellum / Q000002:abnormalities / Q000254:growth & development* / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D051379:Mice; D018345:Mice, Knockout; D009069:Movement Disorders / Q000235:genetics; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010841:Pia Mater / Q000502:physiology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D043562:Receptors, G-Protein-Coupled; C524781:Adgrg1 protein, mouse