Molecular Mechanisms of Cerebral Cortical Patterning

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DESCRIPTION (provided by applicant): My long term goal is to understand the mechanisms that initiate development of the mammalian cerebral cortex and control the formation of the cortical area map, the basic functional organization of the cortex. Findings should be relevant to understanding a wide variety of cortical birth defects, and diseases with later onset that stem from early cortical abnormalities. I propose here to continue a fruitful line of research in which my research group found that the secreted signaling molecule FGF8 regulates patterning of the cortical area map along the anterior/posterior (A/P) axis of the cortical primordium. This proposal has three aims. The first aim is to understand the A/P patterning signal better. At present we do not know if FGF8 and members of the same FGF subfamily form a signaling gradient to impart positional values to the cortex, or if they trigger a relay of other patterning mechanisms. Using mouse genetics we will generate mice with progressively lower levels of FGF8 subfamily ligands to determine if the cortical area map shows increasing shifts. If so, this would provide support for a gradient model, and discount the simplest relay model. To determine which FGF receptors relay the patterning signal, mice that lack combinations of FGF receptors will be analyzed to determine if their cortical maps show defects similar to an FGF8 deficiency. Because FGF/FGFR binding requires heparan sulfate (HS), we will evaluate the cortical area map in mice that lack HS in the cerebral cortex. Although other growth factors require HS, we want to know how loss of FGF signaling will affect area patterning. Will the map be homogenized, or will a default pattern be present? In Aim 2 we will use in utero electroporation of dominant negative FGFRs to determine if cortical cells detect levels of FGF signaling at a distance from the FGF8 source, and, when these levels change, respond by adopting a new area fate. We will also introduce a second source of FGF8 by electroporation and determine if multiple areas are duplicated, and if so, whether and how duplicate maps are ordered along a secondary A/P axis. In Aim 3, we will test the hypothesis that FGF signaling is also involved in the primary division of the telencephalon into the dorsal cerebral cortex and the nuclei of the basal forebrain. We will use mouse genetics, in utero electroporation, and attempted rescue of mouse mutants with excess FGFs to test whether FGF signaling suppresses the cortical fate and promotes ventral telencephalic fates.