Genomes and Genes
Examining the role of the Lissencephaly Protein, Lis1, in Dynein-Based Transport
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
- Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cellsSachin 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...
- A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axonsJai 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...
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