Neuronal migration is a critical step in forming the laminar structure of the visual cortex, but the molecular signals that guide migration and determine final neuronal position are unknown. To determine the role of extracellular matrix (ECM) components in these processes, we have analyzed their spatiotemporal distribution in the cortex of the mouse. Our recent findings are: i) The ECM glycoprotein fibronectin (FN) is distributed along the processes of radial glia where they pass through the preplate/subplate neurons; both FN and chondroitin sulfate proteoglycans (CSPGs) are closely associated with these neurons. These observations suggest that ECM of radial glia is involved in glial-guided migration, and that the ECM surrounding preplate/subplate neurons is a framework for cortical plate formation. ii) Arriving thalamic afferent axons follow a path through the subplate that contains abundant CSPGs, suggesting that CSPGs help to determine the molecular specificity of the pathway. iii) FN is produced in two distinct phases of cortical development, first by cells of the neuroepithelium which include radial glia, and then by a subset of migrating neurons as they approach and enter the cortical plate. To test hypotheses regarding the functional role of ECM components in neuronal migration, we have developed an organotypic slice preparation that preserves embryonic layers, radial glia, and ECM components for several days in a serum-free medium. Neurons divide in the ventricular zone and migrate into the cortical plate in this preparation, and antibodies penetrate the slice. As the next stage of the analysis we will further characterize specific extracellular matrix components present in the developing visual cortex and determine which cells produce individual components. We will use the organotypic slice preparation to determine which cell-surface and extracellular matrix components play a role in neuronal migration by perturbing their function experimentally. Definition of the cellular and -molecular mechanisms underlying neuronal migration will provide a foundation for understanding the abnormalities of cortical lamination that are common manifestations of insults to the brain in early human development.
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