title: Crucial Role of Rapgef2 and Rapgef6, a Family of Guanine Nucleotide Exchange Factors for Rap1 Small GTPase, in Formation of Apical Surface Adherens Junctions and Neural Progenitor Development in the Mouse Cerebral Cortex.
abstract: Cerebral neocortex development in mammals requires highly orchestrated events involving proliferation, differentiation, and migration of neural progenitors and neurons. Rapgef2 and Rapgef6 constitute a unique family of guanine nucleotide exchange factors for Rap1 small GTPase, which is known to play crucial roles in migration of postmitotic neurons. We previously reported that conditional knockout of Rapgef2 in dorsal telencephalon (Rapgef2-cKO) resulted in the formation of an ectopic cortical mass (ECM) resembling that of subcortical band heterotopia. Here we show that double knockout of Rapgef6 in Rapgef2-cKO mice (Rapgef2/6-dKO) results in marked enlargement of the ECM. While Rapgef2-cKO affects late-born neurons only, Rapgef2/6-dKO affects both early-born and late-born neurons. The Rapgef2-cKO cortex at embryonic day (E) 15.5, and the Rapgef2/6-dKO cortex at E13.5 and E15.5 show disruption of the adherens junctions (AJs) on the apical surface, detachment of radial glial cells (RGCs) from the apical surface and disorganization of the radial glial fiber system, which are accompanied by aberrant distribution of RGCs and intermediate progenitors, normally located in the ventricular zone and the subventricular zone, respectively, over the entire cerebral cortex. Moreover, intrauterine transduction of Cre recombinase into the Rapgef2(flox/flox) brains also results in the apical surface AJ disruption and the RGC detachment from the apical surface, both of which are effectively suppressed by cotransduction of the constitutively active Rap1 mutant Rap1(G12V). These results demonstrate a cell-autonomous role of the Rapgef2/6-Rap1 pathway in maintaining the apical surface AJ structures, which is necessary for the proper development of neural progenitor cells.
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maeta
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Edamatsu
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nishihara
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ikutomo
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Shymaa E
authors.initials: SE
authors.lastname: Bilasy
authors.affiliation: Department of Biochemistry and Molecular and Biology, Division of Molecular Biology, Kobe University Graduate School of Medicine , Kobe 650-0017, Japan.
authors.forename: Tohru
authors.identifier: 0000-0001-5450-3840
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001973:Bromodeoxyuridine; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D018274:Electroporation; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C508086:CNrasGEF protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C588099:Rapgef6 protein, mouse; C000620839:Rap1 protein, mouse; D020827:rap1 GTP-Binding Proteins; D001973:Bromodeoxyuridine
keywords: Rap1 small GTPase; Rapgef2; Rapgef6; adherens junction; neocortex development; neural progenitors