Structural hippocampal and neocortical abnormalities underlie many cases of pediatric and adult epilepsy and these structures are required for learning and memory. Subtle defects of hippocampal development are also associated with mental retardation, autism, spectrum disorders and schizophrenia. 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 this 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 three specific aims - (1) Regulation of dentate granule cell production by Wnt/beta-catenin signaling; (2) Wnt signaling functions in neocortical development; (3) Determine the functions of Frizzled9 and 10 in the developing cortex. The methodologies used to pursue these aims include the analysis of LRP6 mutant mice, the production and study of LRP6/Lefl double mutant mice, the production of transgenic mice misexpressing dominant-negative LRP6 throughout the cortex, targeting of two Wnt receptors expressed in the early hippocampus to produce mutant mice for Frizzled 9 and 10 and the generation of transgenic mice misexpressing Frizzled9 throughout the cortex. These experiments should produce a more full understanding of the processes regulated by Wnts in the developing hippocampus and neocortex.
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