Major migratory events that take place during the development of the visual cortex define its structure, and thereby determine its function. The central goal of this project is to understand the molecular signals that lead to the systematic formation of layers in the visual cortex and guide the axons that innervate it. During cortical development, controlled numbers of neurons migrate along radial glia to form layers that have distinct connectional patterns and function, and growth cones of cortical efferent and afferent axons move through defined pathways to reach their targets. The cellular and molecular signals that control these vents are not well understood; defining them is an essential step in understanding the disruptive abnormalities that occur in human cortical development. In our prior studies we have identified specific extracellular matrix (ECM) components that are produced by migrating neurons and thalamocortical axons, and are expressed in axonal pathways. In the present proposal we will test hypotheses regarding the function of these ECM components and their receptors in neurons al and growth cone migration, and determine how a neurotrophin controls the size of an important population of ECM-producing neurons. In these studies we will carry out experimental perturbations in organotypic slice preparations that preserve the three dimensional structure of developing cortex for several days, as well as in dissociated cell culture and in vivo. We will use computer-aided cell recognition techniques to measure migratory distances of labeled neuronal cohorts, and perturb ECM/receptor function with peptide fragments, antibodies, transfected dominant-negative gene constructs, and fusion proteins derived from a gene that is critical in cortical lamination.
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