During development, proliferating cells of the cortical neuroepithelium generate young neurons that migrate from their site of origin into distinct positions within the cortex and assemble into organized neuronal circuits. Defects in the production and migration of cortical neurons have fundamental implications for mental health since migration disorders have been implicated in schizophrenia and bipolar affective illness. Our research explores the cellular and molecular processes by which neural progenitor cells in the mammalian cerebral cortex produce young neurons that migrate to appropriate positions within the brain. Three specific issues are under study: 1) What proteins are localized asymmetrically in mitotic progenitor cells? The PDZ protein mLin-7 is localized apically in progenitor cells and forms a stable complex with mLin-2 and mLin-10. In C. elegans this complex is required for vulval fate induction and localization of the EGF receptor LET-23. We will identify proteins associated with the mLin-7 complex in neural progenitors and use dominant negative forms of mLin-7 to test the function of the complex. 2) What molecules regulate intrinsic differences in progenitor cells over time? Intrinsic changes in progenitor cells affect the types and numbers of neurons and glia produced in the developing forebrain. We will use cell purification techniques, cDNA arrays, and expression profiling methods to identify the cell-intrinsic molecular programs that operate in progenitor cells at distinct stages of cortical development. 3) How does Doublecortin regulate the migration of young neurons in the developing cerebral cortex? Doublecortin is an X-linked gene that encodes a microtubule-associated protein required for normal neuronal migration in the human cortex. We hypothesize that the subcellular localization and function of Doublecortin in migrating neurons is regulated by the serine/threonine kinase MARK/PAR1. We will explore how MARK/PAR1 regulates the localization and function of Doublecortin in migrating neurons. These experiments will provide us with information about the cellular and molecular mechanisms of neurogenesis and migration in the developing cerebral cortex. Studies of normal development will provide insights into the ontogeny of developmental brain disorders in humans, and ultimately suggest strategies for the appropriate treatment of such disorders
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