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Worzfeld, T.* ; Swiercz, J.M.* ; Sentürk, A.* ; Genz, B.* ; Korostylev, A. ; Deng, S.* ; Xia, J.J.* ; Hoshino, M.* ; Epstein, J.A.* ; Chan, A.M.* ; Vollmar, B.* ; Acker-Palmer, A.* ; Kuner, R.* ; Offermanns, S.*

Genetic dissection of plexin signaling in vivo.

Proc. Natl. Acad. Sci. U.S.A. 111, 2194-2199 (2014)
DOI
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
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 contextdependence and functional specificity of individual plexin-mediated signaling pathways during development.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cerebellum ; Neural Tube ; Outflow Tract
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 0
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 111, Heft: 6, Seiten: 2194-2199 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Regeneration Research (IDR)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502300-001
DOI 10.1073/pnas.1308418111
Scopus ID 84893833231
Erfassungsdatum 2014-02-23
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