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beta1 integrin maintains integrity of the embryonic neocortical stem cell niche.

Titlebeta1 integrin maintains integrity of the embryonic neocortical stem cell niche.
Publication TypeJournal Article
Year of Publication2009
AuthorsLoulier K, Lathia JD, Marthiens V, Relucio J, Mughal MR, Tang S-C, Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS, Mattson MP, Haydar TF, ffrench-Constant C
JournalPLoS Biol
Date Published2009 Aug
KeywordsAnimals, Cell Adhesion, Cell Differentiation, Cerebral Ventricles, Embryo, Mammalian, Gene Expression Regulation, Developmental, Image Processing, Computer-Assisted, Integrin beta Chains, Laminin, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Neocortex, Neurons, Signal Transduction, Stem Cells

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.

Alternate JournalPLoS Biol.
PubMed ID19688041
PubMed Central IDPMC2720642
Grant ListP30HD40677 / HD / NICHD NIH HHS / United States
R01 NS051852 / NS / NINDS NIH HHS / United States
R01 NS051852 / NS / NINDS NIH HHS / United States
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom