PT - JOURNAL ARTICLE AU - Kazuhiro Maeta AU - Hironori Edamatsu AU - Kaori Nishihara AU - Junji Ikutomo AU - Shymaa E. Bilasy AU - Tohru Kataoka TI - 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 AID - 10.1523/ENEURO.0142-16.2016 DP - 2016 Jun 13 TA - eneuro PG - ENEURO.0142-16.2016 4099 - http://www.eneuro.org/content/early/2016/06/10/ENEURO.0142-16.2016.short 4100 - http://www.eneuro.org/content/early/2016/06/10/ENEURO.0142-16.2016.full AB - 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 post-mitotic neurons. We previously reported that conditional knockout of Rapgef2 in dorsal telencephalon (Rapgef2-cKO) resulted in formation of an ectopic cortical mass (ECM) resembling that of subcortical band heterotopia. Here we show that additional 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 (VZ) and the subventricular zone, respectively, over the entire cerebral cortex. Moreover, intrauterine transduction of Cre recombinase into the Rapgef2flox/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 co-transduction of the constitutively active Rap1 mutant, Rap1G12V. 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.Significance Statement: Rapgef2 is known to play a critical role in multipolar-bipolar transition of post-mitotic neurons from shRNA-mediated knockdown experiments. This function of Rapgef2 was presumed to account for the formation of an ectopic cortical mass observed in Rapgef2 conditional knockout (Rapgef2-cKO) mice. In this manuscript, by utilizing Rapgef2-cKO mice and the intrauterine electroporation method, we are able to demonstrate a novel role of the Rapgef2-Rap1 pathway in proper development of neural progenitors, particularly RGCs, which is presumably accounted for by its cell-autonomous role in maintaining the apical surface AJ structures. Moreover, we show that Rapgef6, a close Rapgef2 homologue implicated in the etiology of schizophrenia, shares some of these functions with Rapgef2 from the examination of Rapgef2/6 double knockout mice.