The overall goal of this project is to understand the molecular mechanisms by which the mature visual cortex is formed from a relatively simple proliferative neuroepithelium. To achieve this goal, it is proposed to identify and study a number of genes and gene products that may regulate or mark the formation of cytoarchitectonic areas and individual cell types. The neurons of the preplate are clearly an important component of overall cortical development. One of the specific aims of this proposal is to complete the biochemical characterization of a molecule whose expression in the developing nervous system is restricted to a subpopulation of subplate neurons. Experiments are also proposed to determine whether expression of this molecule is linked to cell death in this layer. To characterize further the formation of cell types in both preplate and cortical plate, specific monoclonal antibodies will be produced against partially purified immunogens consisting of subplate cells or microdissected layers of adult visual cortex. In addition the spatial and temporal distribution of a series of molecules involved the production and action of cGMP will be measured by in situ hybridization. These molecules will be studied because several of them have been implicated in events of cortical development and plasticity. Delineation of cortical areas and formation of cortical cell types is almost certainly regulated by differential expression of transcription factors. Following up on preliminary experiments, it is proposed to carry out a systematic search for members of the POU-domain and helix-loop-helix gene families that show differential patterns of expression either in the proliferative epithelium or in its postmitatic derivatives. In a final specific aim it is proposed to study the expression of selected molecules in a series of simplified culture systems. These will allow the identification of properties of cortical assembly that are intrinsic to particular cell types and of molecules whose expression or activity can be modulated by synaptic contacts. By focussing on selected topics within a broad developmental framework this proposal will allow a significant increase in our understanding of the molecular mechanisms of cortical development. The results from this project will have a substantial impact in a number of health-related issues including the response of visual cortex to abnormal visual input and problems associated with many developmental brain abnormalities.
