Abstract

Type I lissencephaly is a severe brain developmental disease which involves defects in neural progenitor cell migration during the formation of the cerebral cortex. It is caused by LIS1 haploinsufficiency, resulting from sporadic mutations in the LIS1 gene. LIS1 has been implicated in the platelet activating factor and cytoplasmic dynein pathways, but current evidence suggests that defects in the latter are responsible for the brain developmental disease. Work from this lab has indicated that LIS1 functions together with cytoplasmic dynein at kinetochores and the cortex of dividing cells, at the leading edge of migrating fibroblasts, and during growth cone remodeling. Recent results from this lab have identified severe effects of LIS1 RNAi on the behavior of neural progenitor cells from neurogenesis through the entire course of radial migration by live imaging of brain slices.
Aim I of this project will be to characterize further functional interactions between LIS1 and cytoplasmic dynein and their mutual binding partners NudE, and NudEL. The role of protein phosphorylation in regulating these interactions, and the effects of LIS1, NudE, and NudEL on dynein mechanochemical activity will be'determined.
Aim II will be to define the role of LIS1, NudE and NudEL in the morphogenesis and locomotion of bipolar neural progenitors.
Aim III will be to define the role of LIS1, NudE and NudEL in the interkinetic nuclear oscillations and cell division cycle of neural progenitor cells at the radial glial stage. Live imaging of embryonic rodent brain slices and isolated neural progenitors will be performed on control, mutant, or RNAi-treated animals to evaluate effects on nucleokinesis, cell division, control of division by nuclear position, glial guided migration, and process dynamics. The behavior of the microtubule cytoskeleton, centrosomes, nuclei, LIS1, NudE, and NudEL will be monitored to understand the underlying cellular causes for observed brain phenotypic effects. These studies are of considerable relevance to understanding normal and abnormal brain development, cell migration, cell division, the causes of mental retardation, and stem cell behavior.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD040182-09
Application #
7548168
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Vitkovic, Ljubisa
Project Start
2000-08-01
Project End
2011-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
9
Fiscal Year
2009
Total Cost
$323,976
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

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
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
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

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