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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711840.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Genetic dissection of plexin signaling in vivo
Authors:Worzfeld, T.; Swiercz, J. M.; Senturk, A.; Genz, B.; Korostylev, A.; Deng, S.; Xia, J.; Hoshino, M.; Epstein, J. A.; Chan, A. M.; Vollmar, B.; Acker-Palmer, A.; Kuner, R.; Offermanns, S.
Date of Publication (YYYY-MM-DD):2014-02-11
Title of Journal:Proc Natl Acad Sci u S A
Issue / Number:6
Start Page:2194
End Page:2199
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Animals; Mice; Mice, Transgenic; Nerve Tissue Proteins/*metabolism; Signal Transduction/*genetics
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822116
Identifiers:ISSN:1091-6490 (Electronic) 0027-8424 (Linking) %R 10.1073/pnas.1308418111
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