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Peering into Stem Cells in Live Brain: Interdisciplinary Approaches to Study Neural Development and Disorder Jin-Wu Tsai1 1 Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Abstract: The vertebrate central nervous system (CNS) originates from neural stem cells composed of highly organized neuroepithelial and, subsequently, radial glial cells, which give rise to virtually all neurons in the brain. During development, these neural stem cells and their progeny go through a series of motile events, including migration, morphogenesis, and neurite outgrowth. Any small perturbation in these processes can cause neural developmental disorders, such as lissencephaly, microcephaly, double cortex, schizophrenia, and even autism. In order to study the etiology of these developmental disorders, we established animal models to elucidate the functions of their causal genes in vivo. For example, we used in utero electroporation of shRNA constructs into embryonic neural stem cells to knock down the expression of LIS1, mutations of which lead to lissencephaly. We found that knockdown of LIS1 completely blocks the interkinetic nuclear migration (INM), as well as the subsequent radial migration of committed neuronal precursors (J Cell Biol, 176:935). We further developed a culture system to observe neural cells in brain slices using high resolution light microscopy. Live imaging of coexpressed histone, centrosome, and microtubule plus-end markers revealed that LIS1 is required for both nuclear and centrosome movement in the radially migrating cells (Nat Neurosci, 10:970). We have also applied these approaches to the behavior of neural stem cells and found that INM involve a cell cycle-dependent switch between dynein- and nonconventional kinesin-driven nuclear transport (Nat Neurosci, 13:1463). We now used in vivo cerebellar eleccroporation to label and manipulate gene expression in cerebellar granule neuron progenitors (GNPs) and investigate the molecular mechanisms of neural stem cell proliferation, differentiation and migration during cerebellar development. These approaches can be expanded to elucidate the mechanism of normal brain development and shed light on how various genes cause many neural developmental disorders. 1