Plexin-B2 Controls the Development of Cerebellar Granule Cells

Friedel, Roland H.; Kerjan, Géraldine; Rayburn, Helen; Schüller, Ulrich; Sotelo, Constantino; Tessier‐Lavigne, Marc; Chédotal, Alain

doi:10.1523/jneurosci.4710-06.2007

Cited by 70 publications

(106 citation statements)

References 70 publications

(72 reference statements)

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“…Plxnb2 knockout mice (plxnb2 −/− ) display neural tube closure defects, which result in exencephaly and perinatal lethality (23,24). A small proportion of mice (∼5%) bypasses this neural tube closure phenotype and demonstrates abnormalities in cerebellar granule cell migration and defects in corticogenesis and migration of neuroblasts in the subventricular zone (23)(24)(25)(26). In our effort to understand which signaling functions of Plexin-B2 are relevant in vivo, we first generated BAC transgenic mice that express triple-myc-tagged wild-type Plexin-B2 (BAC B2WT).…”

Section: Resultsmentioning

confidence: 99%

Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.neural tube | cerebellum | outflow tract P lexins constitute a family of transmembrane proteins that serve as receptors for semaphorins (1). They function as key regulators of a multitude of developmental processes, including axon guidance, pattern and synapse formation in the nervous system (2), vasculogenesis and angiogenesis (3, 4), and morphogenesis of the heart, kidney, and skeletal system (5). In the adult organism, plexins play crucial roles in the physiology and pathophysiology of the immune and cardiovascular system, as well as in bone homeostasis and in cancer (6-9). Nine plexins have been identified in the mammalian system, which are grouped into four subfamilies, A-D, according to sequence homologies.The activation of plexins by their semaphorin ligands triggers several intracellular signaling cascades, most of which modulate the activity of small GTPases (10). The intracellular domain of all plexins shares homology with GTPase-activating proteins (GAPs) and confers the deactivation of R-Ras, M-Ras, and Rap1 (11-17). The GAP activity toward R-Ras and M-Ras, but not toward Rap1, requires binding of Rnd GTPases to the plexin receptor (11,12,15,16). Plexins of the B-subfamily differ from all other plexins in that they carry a C-terminal PDZ domain interaction motif that mediates a stable interaction with the Rho guanine nucleotide exchange factor (RhoGEF) proteins . Activation of B-plexins by semaphorin ligands results in activation of the RhoGEF proteins and subsequent activation of . This process and the GAP function of B-plexins are independent of each other, becau...

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Section: Resultsmentioning

confidence: 99%

Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…It is nonetheless noteworthy that, unlike other signals (such as BDNF, Sema6A, Barhl1, PlexinB2, Jagged1, etc.) whose expression must be near completely eliminated in vivo to impair GC migration (Borghesani et al, 2002;Li et al, 2004;Kerjan et al, 2005;Weller et al, 2006;Friedel et al, 2007), even a relatively small decrease in VEGF levels sufficed to perturb this process. Another consideration is that the spatial VEGF expression pattern leads us to conclude that migration of postmitotic GCs beyond the PCL into the IGL must involve other cues than VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…Using a widely used technique (Borghesani et al, 2002;Vaillant et al, 2003;Chen et al, 2005;Friedel et al, 2007), P10 mice were injected with BrdU to label GCPs and killed 2 d later to analyze the number of BrdU-labeled (BrdU ϩ ) GCs present in the EGL, ML, and IGL. Immunostaining for BrdU was complemented with VEGF immunostaining to confirm the reduced VEGF levels in VEGF Ѩ / Ѩ mice.…”

Section: Granule Cells and Their Growth Cones Are Attracted By Vegfmentioning

confidence: 99%

Matrix-Binding Vascular Endothelial Growth Factor (VEGF) Isoforms Guide Granule Cell Migration in the Cerebellum via VEGF Receptor Flk1

et al. 2010

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Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has important, yet poorly characterized roles in neuronal wiring. Using several genetic and in vitro approaches, we discovered a novel role for VEGF in the control of cerebellar granule cell (GC) migration from the external granule cell layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide for the first time in vivo evidence for a direct chemoattractive effect of VEGF on neurons via Flk1 signaling. Finally, using knock-in mice expressing single VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms around PC dendrites is necessary for proper GC migration in vivo. These findings identify a previously unknown role for VEGF in neuronal migration.

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“…Sema4D-and plexin-B1-deficient on the C57BL/6 background were generated and maintained as described previously (13,22,23). CD72-deficient mice were provided by Dr. Parnes (Stanford University, Stanford, CA) (24).…”

Section: Micementioning

confidence: 99%

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

Okuno

Nakatsuji

Moriya

et al. 2009

The Journal of Immunology

102

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Although semaphorins were originally identified as axonal guidance molecules during neuronal development, it is emerging that several semaphorins play crucial roles in various phases of immune responses. Sema4D/CD100, a class IV semaphorin, has been shown to be involved in the nervous and immune systems through its receptors plexin-B1 and CD72, respectively. However, the involvement of Sema4D in neuroinflammation still remains unclear. We found that Sema4D promoted inducible NO synthase expression by primary mouse microglia, the effects of which were abolished in plexin-B1–deficient but not in CD72-deficient microglia. In addition, during the development of experimental autoimmune encephalomyelitis (EAE), which was induced by immunization with myelin oligodendrocyte glycoprotein-derived peptides, we observed that the expression of Sema4D and plexin-B1 was induced in infiltrating mononuclear cells and microglia, respectively. Consistent with these expression profiles, when myelin oligodendrocyte glycoprotein-specific T cells derived from wild-type mice were adoptively transferred into plexin-B1–deficient mice or bone marrow chimera mice with plexin-B1–deficient CNS resident cells, the development of EAE was considerably attenuated. Furthermore, blocking Abs against Sema4D significantly inhibited neuroinflammation during EAE development. Collectively, our findings demonstrate the role of Sema4D–plexin-B1 interactions in the activation of microglia and provide their pathologic significance in neuroinflammation.

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Plexin-B2 Controls the Development of Cerebellar Granule Cells

Cited by 70 publications

References 70 publications

Genetic dissection of plexin signaling in vivo

Genetic dissection of plexin signaling in vivo

Matrix-Binding Vascular Endothelial Growth Factor (VEGF) Isoforms Guide Granule Cell Migration in the Cerebellum via VEGF Receptor Flk1

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

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