Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression

• Published in: Biochemical and biophysical research communications 2017-11, Vol.493 (1), p.139-145
• Main Authors: Farag, Maged Ibrahim, Yoshikawa, Yoko, Maeta, Kazuhiro, Kataoka, Tohru
• Format: Article
• Language: English
• Subjects: Adherence junction; Adherens Junctions - physiology; Adherens Junctions - ultrastructure; Animals; Cells, Cultured; Ependymoglial Cells - metabolism; Ependymoglial Cells - ultrastructure; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Guanine Nucleotide Exchange Factors - metabolism; MAP Kinase Signaling System - physiology; Mice; Mice, Knockout; Radial glial cells; Rap1; Rapgef2; Small GTPase; Up-Regulation - physiology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.09.062

Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex. The results show that Rapgef2-deficient RGCs exhibit a decreased ability of neurosphere formation, morphological changes represented by regression of radial glial (RG) fibers and reduced expression of AJ-constituent proteins such as N-cadherin, zonula occludens-1, E-cadherin and β-catenin. Moreover, siRNA-mediated knockdown of Rapgef2 or Rap1A inhibits the AJ protein expression and RG fiber formation while overexpression of Rapgef2, Rapgef6, Rap1AG12V or Rap1BG12V in Rapgef2-deficient RGCs restores them. Furthermore, Rapgef2-deficient RGCs exhibit a reduction in phosphorylation of extracellular signal-regulated kinase (ERK) leading to downregulation of the expression of c-jun, which is implicated in the AJ protein expression. These results indicate a crucial role of the Rapgef2-Rap1A-ERK-c-jun pathway in regulation of the AJ formation in RGCs. •Clarifying a molecular basis for developmental defects in Rapgef2-deficient cortex.•Discovering a novel function of Rapgef2/Rap1A in regulation of AJ protein expression.•Demonstrating a pivotal role of Rapgef2/Rap1A in formation of radial glial fibers.•Clarifying a role of ERK and c-jun in Rapgef2/Rap1A-dependent AJ protein expression.