Richard Belvindrah

Publications (13)62.87 Total impact

• Article: MARK2/Par-1 guides the directionality of neuroblasts migrating to the olfactory bulb.

  Sheyla Mejia-Gervacio, Kerren Murray, Tamar Sapir, Richard Belvindrah, Orly Reiner, Pierre-Marie Lledo
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  ABSTRACT: In rodents and most other mammals studied, neuronal precursors generated in the subventricular zone (SVZ) migrate to the adult olfactory bulb (OB) to differentiate into interneurons called granule and periglomerular cells. How the newborn cells navigate in the postnatal forebrain to reach precisely their target area is largely unknown. However, it is often thought that postnatal neurogenesis recapitulates the neuronal development occurring during embryogenesis. During brain development, intracellular kinases are key elements for controlling cell polarization as well as the coupling between polarization and cellular movement. We show here that the polarity kinase MARK2 maintains its expression in the postnatal SVZ-OB system. We therefore investigated the potential role of this kinase in adjusting postnatal neuroblast migration. We employed mouse brain slices maintained in culture, in combination with lentiviral vector injections designed to label neuronal precursors with GFP and to diminish the expression of MARK2. Time-lapse video microscopy was used to monitor neuroblast migration in the postnatal forebrain from SVZ precursors to cells populating the OB. We found that reduced MARK2 expression resulted in altered migratory patterns and stalled neuroblasts in the rostral migratory stream (RMS). In agreement with the observed migratory defects, we report a diminution of the proportion of cells reaching the OB layers. Our study reveals the involvement of MARK2 in the maintenance of the migratory direction in postnatally-generated neuroblasts and consequently on the control of the number of newly-generated neurons reaching and integrating the appropriate target circuits.
  Molecular and Cellular Neuroscience 10/2011; 49(2):97-103. · 3.66 Impact Factor
• Article: Abnormal neuronal migration changes the fate of developing neurons in the postnatal olfactory bulb.

  Richard Belvindrah, Antoine Nissant, Pierre-Marie Lledo
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  ABSTRACT: Neuronal precursors are continuously integrated into the adult olfactory bulb (OB). The vast majority of these precursor cells originates from the subventricular zone and migrates along the rostral migratory stream (RMS) en route to the OB. This process, called postnatal neurogenesis, results from intricate pathways depending both on cell-autonomous factors and extrinsic regulation provided by the local environment. Using electroporation in postnatal mice to label neuronal precursors with green fluorescent protein (GFP) and to reduce the expression levels of doublecortin (DCX) with short-hairpin (Sh) RNA, we investigated the consequences of impairing migration on the fate of postnatal-formed neurons. First, we showed that electroporation of Dcx ShRNA plasmid efficiently knocks down the expression of DCX and disrupts cells migration along the RMS. Second, we found misplaced anomalous migrating cells that displayed defects in polarity and directionality. Third, patch-clamp recordings performed at 5-7 days post-electroporation (dpe) revealed increased density of voltage-dependent Na(+) channels and enhanced responsiveness to GABA(A) receptor agonist. At later time points (i.e., 12 and 30 dpe), most of the Dcx ShRNA(+) cells developed in the core of the OB and displayed aberrant dendritic length and branching. Additional analysis revealed the formation of GABAergic and glutamatergic synaptic inputs on the mispositioned neurons. Finally, quantifying fate determination by numbering the proportion of GFP(+)/calretinin(+) newborn neurons revealed that Dcx ShRNA(+) cells acquire mature phenotype despite their immature location. We conclude that altering the pace of migration at early stages of postnatal neurogenesis profoundly modifies the tightly orchestrated steps of neuronal maturation, and unveils the influence of microenvironment on controlling neuronal development in the postnatal forebrain.
  Journal of Neuroscience 05/2011; 31(20):7551-62. · 7.11 Impact Factor
• Article: Regulation of radial glial survival by signals from the meninges.

  Randor Radakovits, Claudia S Barros, Richard Belvindrah, Bruce Patton, Ulrich Müller
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  ABSTRACT: Radial glial cells (RGCs) in the developing cerebral cortex are progenitors for neurons and glia, and their processes serve as guideposts for migrating neurons. So far, it has remained unclear whether RGC processes also control the function of RGCs more directly. Here, we show that RGC numbers and cortical size are reduced in mice lacking beta1 integrins in RGCs. TUNEL stainings and time-lapse video recordings demonstrate that beta1-deficient RGCs processes detach from the meningeal basement membrane (BM) followed by apoptotic death of RGCs. Apoptosis is also induced by surgical removal of the meninges. Finally, mice lacking the BM components laminin alpha2 and alpha4 show defects in the attachment of RGC processes at the meninges, a reduction in cortical size, and enhanced apoptosis of RGC cells. Our findings demonstrate that attachment of RGC processes at the meninges is important for RGC survival and the control of cortical size.
  Journal of Neuroscience 07/2009; 29(24):7694-705. · 7.11 Impact Factor
• Article: Postnatal neurogenesis: from neuroblast migration to neuronal integration.

  Richard Belvindrah, Françoise Lazarini, Pierre-Marie Lledo
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  ABSTRACT: Ongoing neurogenesis maintains neuronal replacement in a few regions of the mammalian adult brain. One of these regions, the subventricular zone, generates olfactory bulb interneuron precursors that must migrate through the rostral migratory stream to reach the olfactory bulb circuit. There, they rapidly initiate dendritic growth and establish dendro-dendritic contacts with mitral/tufted cells and potentially other local interneurons. The sequential steps involved in neuroblast maturation during development have been studied extensively over previous years. However, the mechanisms and regulatory factors controlling the recruitment and first steps of synaptic integration of newly-formed neurons in the adult forebrain have only recently started to be elucidated. This review provides an integrated view of our current understanding of fate-choice decision in progenitors, how newborn neurons correctly migrate to specific circuits, how they integrate in olfactory bulb microcircuits, and the function they have to fulfill once they survive. The elucidation of these mechanisms may be crucial to understand the functional role of adult neurogenesis and eventually develop therapeutic strategies aimed at re-routing neuroblasts to altered circuits.
  Reviews in the neurosciences 01/2009; 20(5-6):331-46. · 2.41 Impact Factor
• Article: Beta1 integrins in radial glia but not in migrating neurons are essential for the formation of cell layers in the cerebral cortex.

  Richard Belvindrah, Diana Graus-Porta, Sandra Goebbels, Klaus-Armin Nave, Ulrich Müller
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  ABSTRACT: Radial glial cells in the cerebral cortex serve as progenitors for neurons and glia and guide the migration of cortical neurons. The integrin alpha3beta1 is thought to mediate interactions of migrating neurons with radial glial cells and to function as a receptor for the reelin signaling molecule. Here, we challenge this view and demonstrate that beta1 integrins in migrating neurons are not essential for the formation of cell layers in the cerebral cortex. Cortical cell layers also form normally in mice deficient in the integrin alpha3beta1. However, we provide evidence that beta1 integrins in radial glia control the morphological differentiation of both glia and neurons. We conclude that beta1 integrins in radial glia are required for the proper development of the cerebral cortex, whereas beta1 integrins in migrating neurons are not essential for glial-guided migration and reelin signaling.
  Journal of Neuroscience 01/2008; 27(50):13854-65. · 7.11 Impact Factor
• Article: Mouse CD24 is required for homeostatic cell renewal.

  Vincent Nieoullon, Richard Belvindrah, Geneviève Rougon, Geneviève Chazal
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  ABSTRACT: Under physiological conditions, some adult tissues retain a capacity for self-renewal. This property is attributable to the proliferation and differentiation of stem, transit-amplifying, and differentiating cells, which are regulated by cell-cell or cell-matrix interactions or by secreted factors. By gain and loss of function experiments, we demonstrate the involvement of mouse CD24 (mouse cluster of differentiation 24), which is a glycosyl phosphatidylinositol (GPI)-anchored cell-surface glycoprotein, in the regulation of homeostatic cell renewal. BrdU incorporation observations, at optical and electron-microscopic levels, have revealed increased cell proliferation in the developing brain and in the epithelia of mCD24-deleted mice. We have observed ectopic proliferative cells in the suprabasal layers of the mutant skin leading to a general disruption of basal and suprabasal layers. By contrast, ectopic mCD24 expression mediated by retroviral infection of the embryonic brain leads to a decreased number of clusters of cells generated in the progeny. Together, these results and our previous published data indicate that mCD24 contributes to the regulation of the production of differentiated cells by controlling the proliferation/differentiation balance between transit-amplifying and committed differentiated cells.
  Cell and Tissue Research 10/2007; 329(3):457-67. · 3.11 Impact Factor
• Article: Beta1 integrins control the formation of cell chains in the adult rostral migratory stream.

  Richard Belvindrah, Sabine Hankel, John Walker, Bruce L Patton, Ulrich Müller
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  ABSTRACT: The subventricular zone (SVZ) of the lateral ventricle is the major site of neurogenesis in the adult brain. Neuroblasts that are born in the SVZ migrate as chains along the rostral migratory stream (RMS) to the olfactory bulb. Little is known about the mechanisms that control interactions between neuroblasts during their migration. Here we show that migrating neuroblasts express beta1 integrins and that the integrin ligand laminin is localized to cell chains. Using genetically modified mice and time-lapse video recordings of SVZ explants, we demonstrate that beta1 integrins and laminin promote the formation of cell chains. Laminin also induces the aggregation of purified neuroblasts. We conclude that the formation of cell chains in the RMS is controlled in part by beta1 integrins via binding to laminin. In addition, we provide evidence that beta1 class integrins are required for the maintenance of the glial tubes and that defects in the glial tubes lead to the ectopic migration of neuroblasts into the surrounding tissue.
  Journal of Neuroscience 04/2007; 27(10):2704-17. · 7.11 Impact Factor
• Source

  Available from: PubMed Central

  Article: Beta1-integrin signaling is essential for lens fiber survival.

  Andrew R Samuelsson, Richard Belvindrah, Chuanyue Wu, Uli Müller, Willi Halfter
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  ABSTRACT: Integrins have been proposed to play a major role in lens morphogenesis. To determine the role of beta1-integrin and its down-stream signaling partner, integrin linked kinase (ILK), in lens morphogenesis, eyes of WT mice and mice with a nestin-linked conditional knockout of beta1-integrin or ILK were analyzed for defects in lens development. Mice, lacking the genes encoding the beta1-integrin subunit (Itgb1) or ILK (Ilk), showed a perinatal degeneration of the lens. Early signs of lens degeneration included vacuolization, random distribution of lens cell nuclei, disrupted fiber morphology and attenuation and separation of the lens capsule. The phenotype became progressively more severe during the first postnatal week eventually leading to the complete loss of the lens. A more severe phenotype was observed in ILK mutants at similar stages. Eyes from embryonic day 13 beta1-integrin-mutant embryos showed no obvious signs of lens degeneration, indicating that mutant lens develops normally until peri-recombination. Our findings suggest that beta1-integrins and ILK cooperate to control lens cell survival and link lens fibers to the surrounding extracellular matrix. The assembly and integrity of the lens capsule also appears to be reliant on integrin signaling within lens fibers. Extrapolation of these results indicates a novel role of integrins in lens cell-cell adhesions as well as a potential role in the pathogenesis of congenital cataracts.
  Gene regulation and systems biology 01/2007; 1:177-89.
• Article: Integrin-linked kinase regulates Bergmann glial differentiation during cerebellar development.

  Richard Belvindrah, Perihan Nalbant, Sheng Ding, Chuanyue Wu, Gary M Bokoch, Ulrich Müller
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  ABSTRACT: We demonstrate here that integrin-linked kinase (ILK), a serine/threonine kinase that binds to the beta1 integrin cytoplasmic domain, regulates cerebellar development. Mice with a CNS-restricted knock-out of the Ilk gene show perturbations in the laminar structure of the cerebellar cortex that are associated with defects in Bergmann glial fibers and the formation of meningeal basement membranes. Similar defects have been observed in mice lacking beta1 integrins in the CNS. ILK and beta1 integrins are coexpressed in Bergmann glial cells, and studies with primary cells in culture demonstrate that ILK and CDC42 are required for beta1-integrin-dependent glial process outgrowth. Consistent with these findings, the amount of GTP-bound CDC42 is impaired in the cerebellum of Ilk-deficient mice. We conclude that beta1 integrin, ILK and CDC42 are components of the signaling machinery that regulates glial process outgrowth in the cerebellum. We also show that granule cell precursor proliferation is affected in ILK-deficient mice, but our findings provide strong evidence that proliferative defects are a secondary consequence of ILK function in glia.
  Molecular and Cellular Neuroscience 11/2006; 33(2):109-25. · 3.66 Impact Factor
• Article: mCD24 regulates proliferation of neuronal committed precursors in the subventricular zone.

  Vincent Nieoullon, Richard Belvindrah, Geneviève Rougon, Geneviève Chazal
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  ABSTRACT: We previously showed that deletion of the cell surface molecule mCD24 resulted in an increased proliferation in adult subventricular zone (SVZ). Here, we report an increased PSA-NCAM+/TuJ1- population in the mCD24-/- in vivo SVZ as well as in vitro neurospheres. Isolated in vitro, these cells were able to generate neurospheres. Proliferation studies, using BrdU incorporation, showed an increased proliferation in P7 mCD24-/- SVZ and neurospheres. Using electron microscopy, the same cell types were identified in the in vivo SVZ as well as in vitro neurospheres from the WT and mCD24-/- mice. In mixed neurospheres, formed with WT and EGFP/KO cells (enhanced green fluorescent protein mCD24-/-), the WT environment was able to control the proliferation rate of the mCD24-/- cells, but was unable to regulate their differentiation. We concluded that mCD24 acts cell nonautonomously to regulate transit-amplifying cells proliferation and/or differentiation.
  Molecular and Cellular Neuroscience 04/2005; 28(3):462-74. · 3.66 Impact Factor
• Article: Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis.

  Sandra Pennartz, Richard Belvindrah, Stefan Tomiuk, Céline Zimmer, Kay Hofmann, Marcus Conradt, Andreas Bosio, Harold Cremer
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  ABSTRACT: The progeny of neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain consists in polysialylated NCAM-expressing immature neurons (PSA(+) cells), which migrate to the olfactory bulb (OB) to differentiate into GABAergic interneurons. We purified murine PSA(+) cells directly from the adult brain by FACS and analyzed their gene expression profile by SAGE. Comparative analyses led to the identification of precursor-enriched genes, including Survivin, Sox-4, Meis2, Dishevelled-2, C3aR1 and Riken 3110003A17, and many so far uncharacterized transcripts. Cluster analysis showed that groups of genes involved in axon guidance and gene clusters implicated in chemotaxis are strongly upregulated, indicating a role of both cues in the control of cell migration in the adult brain. Furthermore, genes involved in apoptosis and cell proliferation are co-expressed, suggesting that the amount of precursors that is present in the adult brain is a result of an equilibrium of these processes.
  Molecular and Cellular Neuroscience 05/2004; 25(4):692-706. · 3.66 Impact Factor
• Article: Beta1-integrins are critical for cerebellar granule cell precursor proliferation.

  Sandra Blaess, Diana Graus-Porta, Richard Belvindrah, Randor Radakovits, Sebastian Pons, Amanda Littlewood-Evans, Mathias Senften, Huailian Guo, Yuqing Li, Jeffrey H Miner, Louis F Reichardt, Ulrich Müller
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  ABSTRACT: We have previously shown that mice with a CNS restricted knock-out of the integrin beta1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adult Itgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum of Itgb1-CNSko mice. In the absence of beta1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that beta1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on beta1 integrin expression in GCPs. Taken together, these data are consistent with a model in which beta1 integrin expression in GCPs is required to recruit a laminin-Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.
  Journal of Neuroscience 04/2004; 24(13):3402-12. · 7.11 Impact Factor
• Article: Increased neurogenesis in adult mCD24-deficient mice.

  Richard Belvindrah, Geneviève Rougon, Geneviève Chazal
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  ABSTRACT: mCD24, a glycosylphosphatidylinositol-anchored highly glycosylated molecule, is expressed on differentiating neurons during development. In the adult CNS, its expression is restricted to immature neurons located in two regions showing ongoing neurogenesis: the subventricular zone (SVZ) of the lateral ventricle pathway and the dentate gyrus (DG) of the hippocampal formation. Here, combining bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen labelings we confirmed that mCD24 is expressed on proliferating cells. To determine whether the inactivation of the molecule may affect adult neurogenesis, we analyzed the phenotype of mCD24-deficient mice (mCD24-/-). We labeled cells in S-phase with a pulse, a long, or a cumulative administration of BrdU and analyzed cells in different zones according to their dividing rate (rapid and slow) both in the control and mCD24-/-. We found a significant increase in the number of rapid (in the SVZ and the DG) and slow (in the SVZ) proliferating cells. Cumulative assays revealed a global reduction of the total cell cycle duration of rapidly proliferating precursors of SVZ. We investigated the fate of supernumerary cells and observed an increased number of apoptotic cells (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) in the mutant SVZ. Furthermore, we found no difference in the size of the olfactory bulb between wild-type (WT) and mutant mice. In support, mCD24 deletion did not appear to affect migration in the migratory stream. A comparison of the organization of migrating precursors between WT and mCD24 -/-, both in vivo at the optic and electron microscopic levels and in SVZ cultured explants, did not show any changes in the arrangement of neuroblasts in chain-like structures. Altogether, our data suggest that mCD24 regulates negatively cell proliferation in zones of secondary neurogenesis.
  Journal of Neuroscience 06/2002; 22(9):3594-607. · 7.11 Impact Factor