Defects in neocortical neurogenesis and migration cause severe brain developmental disease. LIS1, mutations in which cause lissencephaly (smooth brain), was the first neuronal migration gene to be identified. LIS1 functions in the cytoplasmic dynein pathway, indicating that microtubule motor proteins play a role in brain development. In earlier work supported by this grant we identified multiple discrete LIS1- and dynein- requiring stages in neurogenesis and migration, leading to a comprehensive model for the cellular basis of classical (type I) lissencephaly. We also found LIS1 to be required for the long-mysterious cell-cycle- dependent interkinetic nuclear migration (INM), a general feature of neuroepithelial and radial glial progenitor cell (RGPC) behavior. We have determined further that INM requires the activity of opposite-directed microtubule motor proteins, the plus end-directed unconventional kinesin Kif1a and cytoplasmic dynein. This model appears to explain the underlying mechanism for INM, and should allow us to address further basic and long-standing questions regarding its function and purpose.
The Specific Aims are to determine the mechanism of nuclear transport by Kif1a;to determine how specific inhibition of basal and apical INM affect cell cycle progression and cell fate;and to determine the mechanisms for cell cycle control of INM using small molecule protein kinase inhibitors and other reagents. These issues have important implications for understanding how brain size, composition, and organization are controlled, and how stem cell proliferation is regulated under normal or neoplastic conditions. The analysis of genes responsible for INM and the use of small molecule cell cycle inhibitors will also identify potential targets for modulating neurogenesis and migration during early brain development.
This proposal addresses the mechanisms responsible for neural progenitor cell behavior in the developing brain. We will test the consequences of inhibiting specific genes and protein kinases on the developmental fate of progenitor cells. These studies will identify important new therapeutic targets for developmental conditions, and elucidate the causes of microcephaly, lissencephaly, and heterotopic disorders.
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|Baffet, Alexandre D; Hu, Daniel J; Vallee, Richard B (2015) Cdk1 Activates Pre-mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem Cells. Dev Cell 33:703-16|
|Taylor, S Paige; Dantas, Tiago J; Duran, Ivan et al. (2015) Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. Nat Commun 6:7092|
|Fiorillo, Chiara; Moro, Francesca; Yi, Julie et al. (2014) Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development. Hum Mutat 35:298-302|
|Hu, Daniel Jun-Kit; Baffet, Alexandre Dominique; Nayak, Tania et al. (2013) Dynein recruitment to nuclear pores activates apical nuclear migration and mitotic entry in brain progenitor cells. Cell 154:1300-13|
|Harms, M B; Ori-McKenney, K M; Scoto, M et al. (2012) Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78:1714-20|
|Vallee, Richard B; McKenney, Richard J; Ori-McKenney, Kassandra M (2012) Multiple modes of cytoplasmic dynein regulation. Nat Cell Biol 14:224-30|
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