Neuronal migration is a critical event in the formation of the laminar structure of the cerebral cortex, but the molecular signals that guide migration and determine neuronal position are not known. In prior studies we have shown that the extracellular matrix (ECM) glycoprotein fibronectin (FN) is distributed along the processes of radial glia as they pass through the layers that contain the preplate/subplate neurons and that chondroitin sulfate proteoglycans (CSPG) are closely associated with these neurons. These findings suggest that FN might be involved in glial-guided migration, and that preplate/subplate neurons and their associated ECM may constitute a framework for formation of the cortical plate, which will become definitive cortex. To test these hypotheses we have developed an assay for neuronal migration in an organotypic slice preparation of developing cortex that preserves three-dimensional cortical structure in vitro for several days. We will use this system to perturb the interactions between labeled migrating cells and the ECM experimentally. To analyze these perturbations quantitatively, we will use the Core microscopic and computer resources of the Program Project to automate the acquisition of high resolution images of labeled cells, plot their positions, and perform statistical correlations. We will also use these resources to analyze the distribution of ECM components, their receptors, and matrix proteases on individual migrating cells. These studies will provide a basis for understanding the abnormalities in neuronal migration that are common in the fetal alcohol syndrome and other insults to the cerebral cortex during early human development, and that have been implicated in the pathogenesis of epilepsy and dyslexia.
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