Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone

Saha, Bhaskar; Ypsilanti, Athéna R.; Boutin, Camille; Cremer, Harold; Chédotal, Alain

doi:10.1523/jneurosci.0344-12.2012

Cited by 57 publications

(56 citation statements)

References 81 publications

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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%

“…This crucial importance of the GAP domain of plexins during mouse development is in line with findings in Drosophila and Caenorhabditis elegans, where the GAP domains of PlexA and PLX-1 have been shown to be critical for development of the nervous system (47,48). Owing to the perinatal lethality of Plexin-B2 and Plexin-D1 GAP domain mutant mice, we could not systematically address the functional significance of the GAP domain at postnatal stages of development or in physiological and pathophysiological processes in the adult [e.g., for Plexin-B2 in the postnatal migration and proliferation of neuroblasts (26) and in wound healing (49), or for Plexin-D1 in postnatal development of the nervous system (34,35) and in angiogenesis (36,50)]. Further studies using mice with floxed alleles crossed to the BAC transgenic and specific Cre mice will be required to address these open questions.…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

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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“…PlexinA1 or PlexinA4 knockdown studies in endothelial cells resulted in prominent rearrangements of the actin cytoskeleton that were accompanied by inhibition of cell proliferation (Kigel et al, 2011). More recently, PlexinB2 has been shown to regulate the proliferation and migration of neuroblasts in the postnatal and adult SVZ (Saha et al, 2012). Consistent with such role for PlexinA1 in forebrain progenitor cells, reduced proliferation and progenitor cell numbers in the cortex, LGE, and MGE of PlexinA1 −/− mice was observed, which would account for the reduction in the number of cortical pyramidal neurons and interneurons and of striatal projection cells in these mice.…”

Section: Discussionmentioning

confidence: 99%

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Andrews

Davidson

Tamamaki

et al. 2015

J of Comparative Neurology

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Cortical interneurons are generated predominantly in the medial ganglionic eminence (MGE) and migrate through the ventral and dorsal telencephalon before taking their final positions within the developing cortical plate. Previously we demonstrated that interneurons from Robo1 knockout (Robo1−/−) mice contain reduced levels of neuropilin 1 (Nrp1) and PlexinA1 receptors, rendering them less responsive to the chemorepulsive actions of semaphorin ligands expressed in the striatum and affecting their course of migration (Hernandez‐Miranda et al. [2011] J. Neurosci. 31:6174–6187). Earlier studies have highlighted the importance of Nrp1 and Nrp2 in interneuron migration, and here we assess the role of PlexinA1 in this process. We observed significantly fewer cells expressing the interneuron markers Gad67 and Lhx6 in the cortex of PlexinA1 −/− mice compared with wild‐type littermates at E14.5 and E18.5. Although the level of apoptosis was similar in the mutant and control forebrain, proliferation was significantly reduced in the former. Furthermore, progenitor cells in the MGE of PlexinA1 −/− mice appeared to be poorly anchored to the ventricular surface and showed reduced adhesive properties, which may account for the observed reduction in proliferation. Together our data uncover a novel role for PlexinA1 in forebrain development. J. Comp. Neurol. 524:518–534, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

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“…However, little is known about the cellular and molecular mechanisms underlying the switch from tangential to radial migration, not only in the postnatal brain, but also during embryonic development. Three extracellular matrix molecules have been related to this process in the OB: Reelin, Tenascin-R, and Prokineticin 2 (Hack et al, 2002;Saghatelyan et al, 2004;Ng et al, 2005). Nevertheless, we are still far from understanding the cellular mechanisms that mediate the transition between the two modes of migration.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Sphingosine 1-Phosphate Receptor 1 Promotes the Switch from Tangential to Radial Migration in the OB

et al. 2015

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Neuroblast migration is a highly orchestrated process that ensures the proper integration of newborn neurons into complex neuronal circuits. In the postnatal rodent brain, neuroblasts migrate long distances from the subependymal zone of the lateral ventricles to the olfactory bulb (OB) within the rostral migratory stream (RMS). They first migrate tangentially in close contact to each other and later radially as single cells until they reach their final destination in the OB. Sphingosine 1-phosphate (S1P) is a bioactive lipid that interacts with cell-surface receptors to exert different cellular responses. Although well studied in other systems and a target for the treatment of multiple sclerosis, little is known about S1P in the postnatal brain. Here, we report that the S1P receptor 1 (S1P1) is expressed in neuroblasts migrating in the RMS. Using in vivo and in vitro gain-and loss-of-function approaches in both wild-type and transgenic mice, we found that the activation of S1P1 by its natural ligand S1P, acting as a paracrine signal, contributes to maintain neuroblasts attached to each other while they migrate in chains within the RMS. Once in the OB, neuroblasts cease to express S1P1, which results in cell detachment and initiation of radial migration, likely via downregulation of NCAM1 and ␤1 integrin. Our results reveal a novel physiological function for S1P1 in the postnatal brain, directing the path followed by newborn neurons in the neurogenic niche.

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Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone

Cited by 57 publications

References 81 publications

Genetic dissection of plexin signaling in vivo

Genetic dissection of plexin signaling in vivo

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Downregulation of Sphingosine 1-Phosphate Receptor 1 Promotes the Switch from Tangential to Radial Migration in the OB

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