Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo.
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.
Deng
Suhua
S
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.
Hirschberg
Alexandra
A
Worzfeld
Thomas
T
Penachioni
Junia Y
JY
Korostylev
Alexander
A
Swiercz
Jakub M
JM
Vodrazka
Peter
P
Mauti
Olivier
O
Stoeckli
Esther T
ET
Tamagnone
Luca
L
Offermanns
Stefan
S
Kuner
Rohini
R
D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D019556:COS Cells; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009420:Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D016548:Prosencephalon / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; C519231:Plxnb2 protein, mouse; D011956:Receptors, Cell Surface