Genetic dissection of plexin signaling in vivo

• Verfasst von: Worzfeld, Thomas [VerfasserIn]
• Verfasst von: Swiercz, Jakub Michal [VerfasserIn]
• Verfasst von: Senturk, Aycan [VerfasserIn]
• Verfasst von: Genz, Berit [VerfasserIn]
• Verfasst von: Korostylev, Alexander [VerfasserIn]
• Verfasst von: Deng, Suhua [VerfasserIn]
• Verfasst von: Xia, Jingjing [VerfasserIn]
• Verfasst von: Hoshino, Mikio [VerfasserIn]
• Verfasst von: Epstein, Jonathan A. [VerfasserIn]
• Verfasst von: Chanen, Andrew M. [VerfasserIn]
• Verfasst von: Vollmar, Brigitte [VerfasserIn]
• Verfasst von: Acker-Palmer, Amparo [VerfasserIn]
• Verfasst von: Kuner, Rohini [VerfasserIn]
• Verfasst von: Offermanns, Stefan [VerfasserIn]
• Titel: Genetic dissection of plexin signaling in vivo
• Verf.angabe: Thomas Worzfeld, Jakub M. Swiercz, Aycan Sentürk, Berit Genz, Alexander Korostylev, Suhua Deng, Jingjing Xia, Mikio Hoshino, Jonathan A. Epstein, Andrew M. Chan, Brigitte Vollmar, Amparo Acker-Palmer, Rohini Kuner, and Stefan Offermanns
• E-Jahr: 2014
• Jahr: January 2, 2014
• Umfang: 6 S.
• Fussnoten: Gesehen am 05.10.2020
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2014
• Band/Heft Quelle: 111(2014), 6, Seite 2194-2199
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1308418111
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cerebellum
• Sach-SW: neural tube
• Sach-SW: outflow tract
• K10plus-PPN: 1734632070

Abstract

Mammalian plexins constitute a family of transmembrane receptors for semaphorins and represent critical regulators of various processes during development of the nervous, cardiovascular, skeletal, and renal system. In vitro studies have shown that plexins exert their effects via an intracellular R-Ras/M-Ras GTPase-activating protein (GAP) domain or by activation of RhoA through interaction with Rho guanine nucleotide exchange factor proteins. However, which of these signaling pathways are relevant for plexin functions in vivo is largely unknown. Using an allelic series of transgenic mice, we show that the GAP domain of plexins constitutes their key signaling module during development. Mice in which endogenous Plexin-B2 or Plexin-D1 is replaced by transgenic versions harboring mutations in the GAP domain recapitulate the phenotypes of the respective null mutants in the developing nervous, vascular, and skeletal system. We further provide genetic evidence that, unexpectedly, the GAP domain-mediated developmental functions of plexins are not brought about via R-Ras and M-Ras inactivation. In contrast to the GAP domain mutants, Plexin-B2 transgenic mice defective in Rho guanine nucleotide exchange factor binding are viable and fertile but exhibit abnormal development of the liver vasculature. Our genetic analyses uncover the in vivo context-dependence and functional specificity of individual plexin-mediated signaling pathways during development.