Structural hippocampal and neocortical abnormalities underlie many cases of epilepsy and these structures are required for learning and memory. More subtle defects of hippocampal development are also associated with mental retardation, autism spectrum disorders and schizophrenia and most recently in affective disorders. To understand these disorders it is necessary to improve our basic understanding of the regulation of cortical development. Recent studies show that members of the Wnt family of secreted factors are important in the development of the hippocampus. The hippocampus forms from the neuroepithelium adjacent to a midline organizing structure called the cortical hem. The cortical hem secretes many putative morphogenic factors including a variety of Wnts. Wnt signaling has been demonstrated to regulate hippocampal development, as several lines of mutant mice with defects in Wnt signaling have severe defects in hippocampal development. My primary hypothesis is that Wnt signaling components, including Wnt receptors and effectors control the morphogenesis of the dentate gyrus by controlling proliferation and cell fate of granule cell neurons. My secondary hypothesis is that these signaling components also regulate a variety of developmental processes in other regions of the hippocampus and neocortex. These hypotheses will be addressed by 3 specific aims - 1) Regulation of dentate granule cell production by Wnt/B-catenin signaling;2) Wnt signaling functions in neocortical development;3) Determine the functions of Frizzled9 and 10 in the developing cortex. This proposal represents a continuation of Career Development as an independent scientist. Salary support for these activities is sought in conjunction with an already funded award for these studies but this salary support will cover a large portion of the applicant's salary providing the freedom to pursue the scientific goals of the proposal without excess clinical burden. A detailed career development plan is included as a part of the proposal, as is departmental assurance of support in these activities.
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