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The Journal of Neuroscience, June 6, 2007, 27(23):6333-6347; doi:10.1523/JNEUROSCI.5381-06.2007
Development/Plasticity/Repair
Plexin-B2, But Not Plexin-B1, Critically Modulates Neuronal Migration and Patterning of the Developing Nervous System In Vivo
Suhua Deng,1 Alexandra Hirschberg,1 Thomas Worzfeld,1 Junia Y. Penachioni,2 Alexander Korostylev,1 Jakub M. Swiercz,1 Peter Vodrazka,1 Olivier Mauti,3 Esther T. Stoeckli,3 Luca Tamagnone,2 Stefan Offermanns,1 andRohini Kuner1 1Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany, 2Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy, and 3Institute of Zoology, University of Zürich, CH-8057 Zürich, Switzerland
Correspondence should be addressed to either Stefan Offermanns or Rohini Kuner, Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany, Email: stefan.offermanns{at}pharma.uni-heidelberg.de or Email: rohini.kuner{at}pharma.uni-heidelberg.de
Semaphorins and their receptors, plexins, have emerged as important cellular cues regulating key developmental processes. B-type plexins directly regulate the actin cytoskeleton in a variety of cell types. Recently, B-type plexins have been shown to be expressed in striking patterns in the nervous system over critical developmental windows. However, in contrast to the well characterized plexin-A family, the functional role of plexin-B proteins in neural development and organogenesis in vertebrates in vivo is not known. Here, we have elucidated the functional contribution of the two neuronally expressed plexin-B proteins, Plexin-B1 or Plexin-B2, toward the development of the peripheral nervous system and the CNS by generating and analyzing constitutive knock-out mice. The development of the nervous system was found to be normal in mice lacking Plexin-B1, whereas mice lacking Plexin-B2 demonstrated defects in closure of the neural tube and a conspicuous disorganization of the embryonic brain. After analyzing mutant mice, which bypassed neural tube defects, we observed a key requirement for Plexin-B2 in proliferation and migration of granule cell precursors in the developing dentate gyrus, olfactory bulb, and cerebellum. Furthermore, we identified semaphorin 4C as a high-affinity ligand for Plexin-B2 in binding and functional assays. Semaphorin 4C stimulated activation of ErbB-2 and RhoA via Plexin-B2 and enhanced proliferation and migration of granule cell precursors. Semaphorin 4C-induced proliferation of ventricular zone neuroblasts was abrogated in mice lacking Plexin-B2. These genetic and functional analyses reveal a key requirement for Plexin-B2, but not Plexin-B1, in patterning of the vertebrate nervous system in vivo.
Key words: semaphorin; Rho GTPases; knock-out mice; granule cell; dentate gyrus; cerebellum
Received Dec. 13, 2006; revised April 4, 2007; accepted April 30, 2007.
Correspondence should be addressed to either Stefan Offermanns or Rohini Kuner, Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany, Email: stefan.offermanns{at}pharma.uni-heidelberg.de or Email: rohini.kuner{at}pharma.uni-heidelberg.de
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