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  Genetic dissection of plexin signaling in vivo

Worzfeld, T., Swiercz, J. M., Senturk, A., Genz, B., Korostylev, A., Deng, S., et al. (2014). Genetic dissection of plexin signaling in vivo. Proc Natl Acad Sci U S A, 111(6), 2194-9. doi:10.1073/pnas.1308418111.

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Worzfeld, T., Author
Swiercz, J. M., Author
Senturk, A., Author
Genz, B., Author
Korostylev, A., Author
Deng, S., Author
Xia, J., Author
Hoshino, M., Author
Epstein, J. A., Author
Chan, A. M., Author
Vollmar, B., Author
Acker-Palmer, Amparo1, Author              
Kuner, R., Author
Offermanns, S., Author
Affiliations:
1Neurovascular interface Group, Max Planck Institute for Brain Research, Max Planck Society, ou_2461707              

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Free keywords: Animals Mice Mice, Transgenic Nerve Tissue Proteins/*metabolism Signal Transduction/*genetics cerebellum neural tube outflow tract
 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.

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 Dates: 2014-01-29
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: Other: 24469813
DOI: 10.1073/pnas.1308418111
ISSN: 1091-6490 (Electronic)0027-8424 (Linking)
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Title: Proc Natl Acad Sci U S A
Source Genre: Journal
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Pages: - Volume / Issue: 111 (6) Sequence Number: - Start / End Page: 2194 - 9 Identifier: -