title: Ric-8a, a guanine nucleotide exchange factor for heterotrimeric G proteins, regulates bergmann glia-basement membrane adhesion during cerebellar foliation.
abstract: The cerebellum consists of an intricate array of lobules that arises during the process of foliation. Foliation not only increases surface area, but may also facilitate organization of cerebellar neural circuitry. Defects in cerebellar foliation are associated with a number of diseases. Yet, little is known about how foliation, a process involving large-scale and simultaneous movement of several different cell types, is coordinated by cell-cell signaling at the molecular level. Here we show that Ric-8a, a guanine nucleotide exchange factor in the G-protein-coupled receptor pathway, is specifically required in Bergmann glia during cerebellar foliation. We find that ric-8a mutation in mice results in disorganized Bergmann glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning. These abnormalities result from primary defects in Bergmann glia since mutations in granule cells do not show similar effects. They first arise during late embryogenesis, at the onset of foliation, when ric-8a mutant Bergmann glia fail to maintain adhesion to the basement membrane specifically at emerging fissures. This suggests that Ric-8a is essential for the enhanced Bergmann glia-basement membrane adhesion required for fissure formation. Indeed, we find that ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components. We also find that weakening Bergmann glia-basement membrane interaction by β1 integrin deletion results in a similar phenotype. These results thus reveal a novel role of Ric-8a in modulating Bergmann glia-basement membrane adhesion during foliation, and provide new insights into the signaling pathways that coordinate cellular movement during cerebellar morphogenesis.
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Shang
authors.initials: S
authors.lastname: Ma
authors.forename: Hyo Jun
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002531:Cerebellum / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D020662:Guanine Nucleotide Exchange Factors; D020962:Heterotrimeric GTP-Binding Proteins; D006657:Histones; D019012:Integrin beta1; D007381:Intermediate Filament Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D009479:Neuropeptides; C500943:Atoh1 protein, mouse; C577485:Nes protein, mouse; C104971:Pcp2 protein, mouse; C485884:Ric8a protein, mouse