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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040182-14
Application #
8601915
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Urv, Tiina K
Project Start
2000-08-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
14
Fiscal Year
2014
Total Cost
$295,727
Indirect Cost
$108,977
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Doobin, David J; Kemal, Shahrnaz; Dantas, Tiago J et al. (2016) Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages. Nat Commun 7:12551
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
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
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
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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