Examining the role of the Lissencephaly Protein, Lis1, in Dynein-Based Transport

Summary

Principal Investigator: Deanna S Smith
Abstract: DESCRIPTION (provided by applicant): Lissencephaly, an autosomal dominant brain malformation caused by mutations in the LIS1 gene, was the first neurological disorder linked directly to cytoplasmic dynein function. This discovery led the way for molecular dissection of events regulating development of the mammalian cerebral cortex. Lis1 and a binding partner, Nudel, bind directly to dynein and regulate its activity. This interaction has been studied almost exclusively in the context of brain development. More recently, gene products associated with later-onset disorders such as schizophrenia, amyotrophic lateral sclerosis (ALS), Perry Syndrome, and Huntington's disease (HD) have been shown to interact directly with dynein pathways. The discovery of an important role for Lis1 and Nudel in regulating dynein-dependent axonal transport in cultured adult rat sensory neurons has led to the hypothesis that perturbing this regulatory network will cause neuronal dysfunction in mice. To test this, the pathological consequences of disrupting Lis1 in post-developmentally will be determined using floxed-Lis1 and Cre strains. Histological, biochemical, and behavioral studies will be carried out to determine if depletion of Lis1 post- developmentally causes neurological dysfunction. Because this could exacerbate disease symptoms in lissencephaly and other neurological disorders, these studies may provide a feasible target for clinical intervention by drugs. Possible candidates are the PPAR3 agonists Avandia and Actos, insulin sensitizers normally used to treat type 2 diabetes. Recent studies indicate that these drugs stimulate dynein in several cell lines. This is blocked by mutations in APC, a microtubule plus end associated protein typically linked to colon cancer. APC has also been found to have critical roles in neurons, influencing both synaptic function and axonal transport. Notably, the dynein response to PPAR3 agonists requires PI3K activity and is mimicked by lithium, a potent Gsk32 inhibitor used to treat mood disorders. Moreover, dynein is a target of Gsk32 in vitro and its phosphorylation results in a 5-fold increase in coimmunoprecipitation of an APC fragment suggesting that inhibition of the kinase could impact dynein interactions. Dynein distribution in sensory neurons is altered in response to PPAR3 agonists, leading to the hypothesis that PPAR3 pathways contribute to regulation of dynein-dependent axonal transport in adult neurons. This will be tested by determining the effect of pharmacological and genetic manipulation of PPAR3/Gsk32/APC pathways on organelle transport in adult rat DRG neurons and determining if crosstalk occurs between Lis1 and PPAR3 pathways.
Funding Period: 2006-07-01 - 2017-01-31
more information: NIH RePORT

Top Publications

  1. pmc Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells
    Sachin Hebbar
    Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
    J Cell Biol 182:1063-71. 2008
  2. pmc A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axons
    Jai P Pandey
    Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA
    J Neurosci 31:17207-19. 2011

Research Grants

Detail Information

Publications2

  1. pmc Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells
    Sachin Hebbar
    Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
    J Cell Biol 182:1063-71. 2008
    ..Moreover, prophase cells in the VZ contain elevated levels of Ndel1 phosphorylated at a key cdk5 site. Our data suggest that a delay in NEBD in the VZ could contribute to developmental defects associated with Lis1-Ndel1 disruption...
  2. pmc A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axons
    Jai P Pandey
    Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA
    J Neurosci 31:17207-19. 2011
    ..Our data raise the possibility that defects in a Lis1/Ndel1 regulatory switch could contribute to neurodegenerative diseases linked to axonal pathology in adults...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Engineering inhibitable kinesin motors to study axonal transport
    Kristen J Verhey; Fiscal Year: 2013
    ..This work will provide exciting new insights into how kinesin motors give rise to coordinated transport of protein complexes in cells and will suggest therapeutic targets in human disease. ..
  3. The Interaction of Cytoplasmic Dynein and Dynactin
    Erika L Holzbaur; Fiscal Year: 2013
    ....
  4. Control of dynein transport by cellular factors
    Stephen J King; Fiscal Year: 2013
    ..A greater understanding of the molecular mechanisms of dynein and dynactin dysfunction underlying these diseases may lead to therapeutic intervention for these neurodegenerative diseases. ..
  5. Regulation of Microtubule-based Membrane Traffic by Septin GTPases
    Elias T Spiliotis; Fiscal Year: 2013
    ..g., inhibitory peptides), which can be used as an alternative to microtubule-targeting agents. ..
  6. Molecular and cellular mechanism of Microcephaly
    Arnold Kriegstein; Fiscal Year: 2013
    ....
  7. DYNAMICS OF THE NEURONAL CYTOSKELETON IN AGING BRAIN
    Ralph A Nixon; Fiscal Year: 2013
    ..Defining the specific steps in this regulation will help to clarify mechanisms leading to major neurological diseases, including dementias, and will identify novel cellular targets for developing innovative therapies for these diseases. ..
  8. FRONTOTEMPORAL DEMENTIA: GENES, IMAGES, AND EMOTIONS
    Bruce L Miller; Fiscal Year: 2013
    ..abstract_text> ..
  9. Protein Mass Spectrometry Core Facility for Neuroscience
    Thomas A Neubert; Fiscal Year: 2013
    ....
  10. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
    ..abstract_text> ..
  11. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  12. Mechanisms that Regulate Intracellular Transport
    Thomas S Hays; Fiscal Year: 2013
    ....
  13. Multi-targeted Countermeasures against Acute and Delayed Effects of OP Exposure
    John A Butera; Fiscal Year: 2013
    ..This would set the stage for a final lead optimization campaign focused on identifying pre- clinical leads with well-balanced in vivo PK parameters during an SBIR Phase 2 continuing grant. ..
  14. Molecular motors in cell biology
    Yale E Goldman; Fiscal Year: 2013
    ..We anticipate that the proposed work will take us significantly further toward our goal of understanding motility in the normal and pathological function of cells. ..
  15. IDDRC at Children's Research Institute
    Vittorio Gallo; Fiscal Year: 2013
    ..abstract_text> ..
  16. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  17. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  18. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  19. MICROTUBULE DYNAMICS AND AXON GROWTH
    Peter W Baas; Fiscal Year: 2013
    ..The proposed studies will utilize novel live-cell imaging techniques on cultured neurons, as well as innovative cell biological approaches for manipulating the relevant motor proteins. ..
  20. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  21. Re-wiring of gene expression in the meiotic state
    ALLEN BRUCE FUTCHER; Fiscal Year: 2013
    ..Dr. Leatherwood) The research Projects will be supported by a Microarray Core Facility, which will play a crucial role in all four projects. ..
  22. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  23. Mapping of Neuronal Placement in the Developing Cerebral Cortex
    Eva S Anton; Fiscal Year: 2013
    ....
  24. Regional, Synpatic, Cellular Modulation of Abeta Metabolism
    David M Holtzman; Fiscal Year: 2013
    ..abstract_text> ..
  25. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..
  26. Dynactin function in axons, synapses, and neurodegenerative disease
    Thomas Lloyd; Fiscal Year: 2013
    ..Together these studies will help elucidate the function of the p150 CAP-Gly domain in neurons, and hold promise for shedding light on the mechanisms of cell-type specificity of neurodegenerative disease. ..
  27. Genetics and Cell Biology of Synaptic Development and Function
    Bing Zhang; Fiscal Year: 2013
    ..Further, the synaptic roles for epsin and DLis1 remain poorly understood. Thus, information derived from the proposed studies is expected to have broad biological and clinical significance. ..
  28. Proliferation, Specification &Brain Function
    MARGARET ELIZABETH ROSS; Fiscal Year: 2013
    ..This Program tackles this complexity through the combined efforts of 4 Pis using cutting edge approaches to the elucidation of how developmental signals regulate fate and output of these critically important neurons. ..