β1 Integrin Maintains Integrity of the Embryonic Neocortical Stem Cell Niche

Center for Neuroscience, Children's National Medical Center, Washington, D.C., United States of America.
PLoS Biology (Impact Factor: 9.34). 09/2009; 7(8):e1000176. DOI: 10.1371/journal.pbio.1000176
Source: PubMed


During embryogenesis, the neural stem cells (NSC) of the developing cerebral cortex are located in the ventricular zone (VZ) lining the cerebral ventricles. They exhibit apical and basal processes that contact the ventricular surface and the pial basement membrane, respectively. This unique architecture is important for VZ physical integrity and fate determination of NSC daughter cells. In addition, the shorter apical process is critical for interkinetic nuclear migration (INM), which enables VZ cell mitoses at the ventricular surface. Despite their importance, the mechanisms required for NSC adhesion to the ventricle are poorly understood. We have shown previously that one class of candidate adhesion molecules, laminins, are present in the ventricular region and that their integrin receptors are expressed by NSC. However, prior studies only demonstrate a role for their interaction in the attachment of the basal process to the overlying pial basement membrane. Here we use antibody-blocking and genetic experiments to reveal an additional and novel requirement for laminin/integrin interactions in apical process adhesion and NSC regulation. Transient abrogation of integrin binding and signalling using blocking antibodies to specifically target the ventricular region in utero results in abnormal INM and alterations in the orientation of NSC divisions. We found that these defects were also observed in laminin alpha2 deficient mice. More detailed analyses using a multidisciplinary approach to analyse stem cell behaviour by expression of fluorescent transgenes and multiphoton time-lapse imaging revealed that the transient embryonic disruption of laminin/integrin signalling at the VZ surface resulted in apical process detachment from the ventricular surface, dystrophic radial glia fibers, and substantial layering defects in the postnatal neocortex. Collectively, these data reveal novel roles for the laminin/integrin interaction in anchoring embryonic NSCs to the ventricular surface and maintaining the physical integrity of the neocortical niche, with even transient perturbations resulting in long-lasting cortical defects.

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Available from: Mahendra Surendra Rao, Oct 09, 2015
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    • "Although plasmid DNA exclusively targets radial glia cells during the electroporation process (Boutin et al. 2008), the co-injected antibody may diffuse into the SVZ and target the progeny of radial glia cells. Diffusion of an administered antibody from the LV into deeper layers was demonstrated in embryonic mouse brains supporting this hypothesis (Loulier et al. 2009). Mannitou may otherwise regulate asymmetric cell division of radial glia cells thus generating a reduced number of progeny cells. "
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    ABSTRACT: Protein glycosylation has received much attention due to its multiple functional roles in physiological and pathophysiological conditions. Paucimannose is a common mannosidic N-glycoepitope in invertebrates and plants but has only recently been detected in vertebrates. Herein, we demonstrate the presence of paucimannosidic epitopes specifically in early postnatal neural progenitor cells between postnatal day 0 and 7 in mouse brain suggesting a possible role in the development of neural progenitor cells. Paucimannosidic epitopes were also detected in human glioblastoma cells and human macrophages by immunofluorescence and mass spectrometric analysis. Its expression was significantly increased after proliferation arrest indicating its importance in regulation of cell proliferation. This hypothesis was further strengthened by reduced cell proliferation after application of paucimannose-reactive Mannitou antibody into culture medium of growing cells. Most interestingly, this reduction of cell proliferation upon administration of Mannitou antibody could also be observed in vivo in the subventricular zone of early postnatal mouse brain. Taken together, these observations demonstrate that paucimannosylation directly influences cell proliferation in various vertebrate cell types including early postnatal neural stem cells. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:
    Glycobiology 04/2015; 25(8). DOI:10.1093/glycob/cwv027 · 3.15 Impact Factor
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    • "Grafted cells produced a cloud-like pattern of laminin deposition, which corresponded to the location of neural precursors in both injured and non-injured spinal cord. Given that laminins, particularly those containing the α2 and α5 chains [36], are present in CNS regions where neural stem and progenitor cells reside, both during development and in the adult [34], [35], [58], [59], we hypothesize that laminin can be the molecule produced by hADSCs that mediated the accumulation of neural precursors along the midline and at the injury site. In line with this hypothesis is our previous demonstration that acute injection of the protein laminin alone, as long as it is delivered in its polymeric form, promotes regeneration after spinal cord injury [60]. "
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    ABSTRACT: Cell therapy is a promising strategy to pursue the unmet need for treatment of spinal cord injury (SCI). Although several studies have shown that adult mesenchymal cells contribute to improve the outcomes of SCI, a descripton of the pro-regenerative events triggered by these cells is still lacking. Here we investigated the regenerative properties of human adipose tissue derived stromal cells (hADSCs) in a rat model of spinal cord compression. Cells were delivered directly into the spinal parenchyma immediately after injury. Human ADSCs promoted functional recovery, tissue preservation, and axonal regeneration. Analysis of the cord tissue showed an abundant deposition of laminin of human origin at the lesion site and spinal midline; the appearance of cell clusters composed of neural precursors in the areas of laminin deposition, and the appearance of blood vessels with separated basement membranes along the spinal axis. These effects were also observed after injection of hADSCs into non-injured spinal cord. Considering that laminin is a well-known inducer of axonal growth, as well a component of the extracellular matrix associated to neural progenitors, we propose that it can be the paracrine factor mediating the pro-regenerative effects of hADSCs in spinal cord injury.
    PLoS ONE 05/2014; 9(5):e96020. DOI:10.1371/journal.pone.0096020 · 3.23 Impact Factor
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    • "There are also different temporal and spatial patterns of distribution, which contributes to support the protein as a regulator of neural development (Hunter et al., 1992, Lathia et al., 2007). Laminin has been shown to guide neuronal migration and axonal elongation during maturation of the cortex (Chen et al., 2009), to regulate neurogenesis and survival of radial glia cells (Loulier et al., 2009; Radakovits et al., 2009), and to contribute to proper positioning of neuronal subtypes (Haubst et al., 2006). In the adult brain, laminin has been implicated in the maintenance of the subventricular zone, as well as in proper cell migration in the rostral migratory chain (Belvindrah et al., 2007; Shen et al., 2008). "
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    ABSTRACT: Polylaminin (polyLM) is a flat biomimetic polymer of laminin capable of promoting axonal growth both in vitro and in vivo. It is assembled in a cell-free system when laminin 111 is incubated in acidic pH, whereas incubation in neutral buffer leads to the formation of bulky and irregular polymers (LM). In the present work, we compared the behaviors of cells isolated from the P1 rat retina on polyLM and LM. PolyLM induced cellular spreading and the outgrowth of neurites in contact with the substrate, whereas LM led to the formation of large clusters of cells, with neurites growing only inward. After 24 hr in culture, the number of cells on polyLM increased threefold, and this increase was inhibited by 60% in the presence of the PKA inhibitor H89 and by 41% in the presence of the PKC inhibitor chelerythrine chloride, whereas both inhibitors abolished neuritogenesis. Neither the cell number nor the outgrowth of neurites was affected by the ERK1/2 inhibitor PD98059 on polyLM. On the other hand, PD98059 was able to reduce the cell number on LM, whereas the other inhibitors were not. Immunostaining of P1 retina with an antilaminin antibody revealed that the protein was expressed not only at its inner surface but also within the neuroblast layer in close contact with individual cells. Our results indicate that, when provided in its active polymerized form, laminin can influence both neuritogenesis and proliferation of retinal cells. © 2013 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 01/2014; 92(1):24-34. DOI:10.1002/jnr.23298 · 2.59 Impact Factor
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