The cerebral cortex is a higher brain region with critical motor, sensory, language, and cognitive functions. Developmental abnormalities of the cortex can cause neurologic and psychiatric diseases including epilepsy, mental retardation, and autism. In this proposal for an Independent Scientist Award, the mechanisms that control the laminar fates of cortical neurons (including molecular expression) will be studied. Dr. Hevner is a neuropathologist/neuroscientist who studies cortical development. His immediate career goals are to: 1) establish a vigorous independent research program, 2) expand the repertoire of techniques in his laboratory through collaboration with a more senior expert (Dr. David Price), 3) to increase productivity through enhanced interactions with colleagues at the University of Washington, and 4) to continue enhancing his skills as a neuropathologist and teacher. His long-term career objective is to apply advances in basic research to the understanding, diagnosis, and treatment of diseases affecting the cortex. Dr. Hevner's laboratory and office are located in a modern, well-equipped research facility with animal housing at the Harborview Medical Center (HMC), near the main campus of the University of Washington (UW). HMC and UW support a large community of accomplished developmental neuroscientists, and offer an abundance of available courses, seminars, journal clubs, and presentations. Previous studies have shown that each layer of the cortex contains projection neurons related by similarities of cell size, axonal connections, and molecular expression. The expression of these properties is closely correlated with cell birth date, but mechanisms are unclear and some properties may be regulated post-mitotically. This proposal tests the hypothesis that layer-specific molecular expression can be regulated post-mitotically. Newly generated post-mitotic neurons will be transplanted into the cortex of control (same age) embryos, heterochronic (different age) embryos, or Rein mutant embryos, which lack Reelin and have a disorganized cortex. The molecular expression of transplanted cells will then be examined using a panel of layer-specific markers. If molecular fates are aEered in heterochronic or Rein mutant cortex, this would suggest that certain aspects of laminar fate can be regulated post-mitotically.
