Genetic dissection of plexin signaling in vivo.
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.
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Thomas
T
Worzfeld
Jakub M
JM
Swiercz
Aycan
A
Sentürk
Berit
B
Genz
Alexander
A
Korostylev
Suhua
S
Deng
Jingjing
J
Xia
Mikio
M
Hoshino
Jonathan A
JA
Epstein
Andrew M
AM
Chan
Brigitte
B
Vollmar
Amparo
A
Acker-Palmer
Rohini
R
Kuner
Stefan
S
Offermanns
D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
D009419:Nerve Tissue Proteins; C519231:Plxnb2 protein, mouse
cerebellum; neural tube; outflow tract