Α6 Integrin Subunit Regulates Cerebellar Development (original) (raw)
Related papers
Wiley eBooks, 2010
During cerebral cortex development, post-mitotic neurons interact with radial glial fibers and the extracellular environment to migrate away from the ventricular region and form a correct laminar structure. Integrin receptors are major mediators of cell-cell and cellextracellular matrix interactions. Several integrin heterodimers are present during formation of the cortical layers. The a5b1 receptor is expressed in the neural progenitors of the ventricular zone during cerebral cortex formation. Using in utero electroporation to introduce short hairpin RNAs in the brain at embryonic day 15.5, we were able to inhibit acutely the expression of a5 integrin in the developing cortex. The knockdown of a5 integrin expression level in neural precursors resulted in an inhibition of radial migration, without perturbing the glial scaffold. Moreover, the same inhibitory effect on neuronal migration was observed after electroporation of a Cre recombinase expression plasmid into the neural progenitors of conditional knockout mice for a5 integrin. In both types of experiments, the electroporated cells expressing reduced levels of a5 integrin accumulated in the premigratory region with an abnormal morphology. At postnatal day 2, ectopic neurons were observed in cortical layer V, while a deficit of neurons was observed in cortical layer II-IV. We show that these neurons do not express a layer V-specific marker, suggesting that they have not undergone premature differentiation. Overall, these results indicate that a5b1 integrin functions in the regulation of neural morphology and migration during cortical development, playing a role in cortical lamination.
European Journal of Neuroscience, 2010
During cerebral cortex development, post-mitotic neurons interact with radial glial fibers and the extracellular environment to migrate away from the ventricular region and form a correct laminar structure. Integrin receptors are major mediators of cell-cell and cellextracellular matrix interactions. Several integrin heterodimers are present during formation of the cortical layers. The a5b1 receptor is expressed in the neural progenitors of the ventricular zone during cerebral cortex formation. Using in utero electroporation to introduce short hairpin RNAs in the brain at embryonic day 15.5, we were able to inhibit acutely the expression of a5 integrin in the developing cortex. The knockdown of a5 integrin expression level in neural precursors resulted in an inhibition of radial migration, without perturbing the glial scaffold. Moreover, the same inhibitory effect on neuronal migration was observed after electroporation of a Cre recombinase expression plasmid into the neural progenitors of conditional knockout mice for a5 integrin. In both types of experiments, the electroporated cells expressing reduced levels of a5 integrin accumulated in the premigratory region with an abnormal morphology. At postnatal day 2, ectopic neurons were observed in cortical layer V, while a deficit of neurons was observed in cortical layer II-IV. We show that these neurons do not express a layer V-specific marker, suggesting that they have not undergone premature differentiation. Overall, these results indicate that a5b1 integrin functions in the regulation of neural morphology and migration during cortical development, playing a role in cortical lamination.
β1-Integrins Are Critical for Cerebellar Granule Cell Precursor Proliferation
The Journal of Neuroscience, 2004
We have previously shown that mice with a CNS restricted knock-out of the integrin β1 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 adultItgb1-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 ofItgb1-CNSko mice. In the absence of β1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely.In vitrostudies provide evidence thatβ1 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 dire...
1-Integrins Are Critical for Cerebellar Granule Cell Precursor Proliferation
Journal of Neuroscience, 2004
We have previously shown that mice with a CNS restricted knock-out of the integrin β1 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 β1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence thatβ1 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 β1 integrin expression in GCPs. Taken together, these data are consistent with a model in which β1 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.
The Journal of Neuroscience, 2007
Radial glial cells in the cerebral cortex serve as progenitors for neurons and glia and guide the migration of cortical neurons. The integrin α3β1 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 β1 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 α3β1. However, we provide evidence that β1 integrins in radial glia control the morphological differentiation of both glia and neurons. We conclude that β1 integrins in radial glia are required for the proper development of the cerebral cortex, whereas β1 integrins in migrating neurons are not essential for glial-guided migration and reelin signaling.
Journal of Neuroscience, 2006
We used Cre recombinase (Cre)-loxP technology to study CNS restricted knock-out of the ilk gene by either Nestin-driven or gfap-driven Cre-mediated recombination. Developmental changes in ilk-excised brain regions are similar to those observed in mice lacking the integrin 1 subunit in the CNS, including defective laminin deposition, abnormal glial morphology, and alterations in granule cell migration.
Molecular and Cellular Neuroscience, 2004
Early inductive signals within the embryonic mammalian forebrain establish two major germinal regions along the dorsal-ventral axis. The dorsal germinal zone eventually forms the cerebral cortex while the ventral ganglionic eminence primarily forms the striatum and globus pallidus. The mechanisms leading to patterning of specific forebrain structures from these distinct germinal regions are not fully understood but may involve the adhesive and migratory properties of regionally specified cells and their interactions with the extracellular environments in which they reside. In the present study, we isolated ganglionic eminence neural progenitor cells (geNPC), precursors of the adult striatum, from the ventral forebrain germinal zone and analyzed adhesion, migration, and differentiation of geNPC on various extracellular matrix (ECM) substrates in vitro. Specifically, we evaluated the role of beta1 integrins, a family of cell surface receptors important in neural development, in mediating geNPC behavior on ECM molecules expressed in embryonic brain tissue. Adhesion and migration of geNPC were significantly enhanced on laminin (LN) and fibronectin (FN) relative to other ECM substrates. Antibody perturbation experiments revealed that although geNPC express several beta1 integrins (alpha1beta1, alpha2beta1, alpha3beta1, alpha5beta1, alpha6beta1, alphavbeta1), adhesion and migration on LN and FN were primarily mediated by alpha6beta1 and alpha5beta1, respectively, and these interactions were confirmed by biochemical cross-link/extraction procedures. Finally, neuronal differentiation of geNPC was enhanced on LN, indicating a role for LN in geNPC differentiation. beta1 integrin-ECM interactions may contribute to basic mechanisms of striatal development and may explain the potent migratory capacity of geNPC transplanted into the adult brain.
Brain development: Integrins and the Reelin pathway
Current Biology, 2001
Integrins link the extracellular matrix to the intracellular environment. They have been implicated in the Reelin pathway in cortical development. But new genetic studies have revealed that, while β β 1 integrin plays a role in formation of the basement membrane, it is not essential for neuronal migration.
Neuroscience Letters, 1998
Cell-matrix interaction plays an important role during neuronal development, which is demonstrated by comparing wild type (D3)-and b1 integrin-deficient (G201) embryonic stem cell derived neurons. In D3 preparations complex networks of functionally coupled neurons with bi-and multipolar morphologies develop. In contrast, neuronal differentiation is retarded in G201 derived neurons, recognised by limited migration and restricted morphological differentiation. Furthermore, b1 integrin deficiency causes a delay in expression of major neurotransmitters like GABA and glutamate as well as of synaptophysin. These findings indicate a prominent role of b1 integrin for both morphological and chemical differentiation.