A Radial Glia-Specific Role of RhoA in Double Cortex Formation

Cappello, Silvia; Böhringer, Christian; Bergami, Matteo; Conzelmann, Karl‐Klaus; Ghanem, Alexander; Tomassy, Giulio Srubek; Arlotta, Paola; Mainardi, Marco; Allegra, Manuela; Caleo, Matteo; Hengel, Jolanda van; Brakebusch, Cord; Götz, Magdalena

doi:10.1016/j.neuron.2011.12.030

Cited by 154 publications

(203 citation statements)

References 74 publications

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“…In addition to the GAP function common to all plexins, Bfamily plexins can activate the small GTPase RhoA, a central regulator of cytoskeletal dynamics and cell migration that is required for neocortical development (44,45). Our data indicate that Plexin-B2-mediated RhoA activation is dispensable for development of the neocortex.…”

Section: Discussionmentioning

confidence: 81%

“…During development of the nervous system, Plexin-B2 is strongly expressed in the telencephalic ventricular and subventricular zone, as well as in the neuroepithelium of the medial and lateral ganglionic eminences, and mice lacking Plexin-B2 that bypass the neural tube closure defect display severe abnormalities in corticogenesis, including abnormal cortical layering and defective migration and differentiation of several subtypes of cortical neurons (25,41). The small GTPase RhoA plays a key role in the development of the nervous system by regulating a multitude of cellular functions, including cell migration, polarity, and survival (42,43), and regulation of RhoA activity is required for corticogenesis (44,45). To test whether Plexin-B2 exerts its functions in corticogenesis via activation of RhoA, we examined mice in which the endogenous Plexin-B2 was replaced by a Plexin-B2 version defective in RhoGEF binding.…”

Section: Plexin-b2-mediated Rhoa Activation Is Dispensable For Neocormentioning

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: Discussionmentioning

confidence: 81%

Section: Plexin-b2-mediated Rhoa Activation Is Dispensable For Neocormentioning

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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“…Gmip has a Rho-GAP activity 28 and regulates cell morphology in cultured fibroblasts by deactivating RhoA. Although several studies suggested that RhoA is crucial for neuronal migration in the embryonic cerebral cortex [31][32][33][34][35] , neither the spatio-temporal activation pattern of RhoA signalling in the migrating OB neurons nor its regulatory mechanisms has been demonstrated. To study the expression of RhoA, we immunostained cultured new neurons dissociated from postnatal mouse V-SVZ tissues.…”

Section: Identification Of Gmip As a Girdin-interacting Proteinmentioning

confidence: 99%

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA

et al. 2014

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“…Radial glia comprise a molecularly defined cellular population playing critical roles in CNS development as both neural and glial progenitors (8,9) and as scaffolding for migratory neurons (10). They derive from neuroepithelial cells and are first identified in the embryonic brain at the onset of neurogenesis (8,11).…”

mentioning

confidence: 99%

Differential transformation capacity of neuro-glial progenitors during development

Muñoz

Singh

Tung

et al. 2013

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

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Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox-mediated and Tet-regulated expression to drive K-ras G12D expression in neuro-glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-ras G12D -induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-ras G12D expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation. mouse models | temporal specification | lineage | differentiation

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A Radial Glia-Specific Role of RhoA in Double Cortex Formation

Cited by 154 publications

References 74 publications

Genetic dissection of plexin signaling in vivo

Genetic dissection of plexin signaling in vivo

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA

Differential transformation capacity of neuro-glial progenitors during development

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