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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Urv, Tiina K
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Wynne, Caitlin L; Vallee, Richard B (2018) Cdk1 phosphorylation of the dynein adapter Nde1 controls cargo binding from G2 to anaphase. J Cell Biol 217:3019-3029
Baffet, Alexandre D; Carabalona, Aurélie; Dantas, Tiago J et al. (2016) Cellular and subcellular imaging of motor protein-based behavior in embryonic rat brain. Methods Cell Biol 131:349-63
Yi, Julie; Khobrekar, Noopur V; Dantas, Tiago J et al. (2016) Imaging of motor-dependent transport in neuronal and nonneuronal cells at high spatial and temporal resolution. Methods Cell Biol 131:453-65
Carabalona, Aurelie; Hu, Daniel Jun-Kit; Vallee, Richard B (2016) KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration. Nat Neurosci 19:253-62
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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
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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
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