[Molecular mechanism of lissencephaly--how LIS1 and NDEL1 regulate cytoplasmic dynein?].
Lissencephaly is a devastating neurological disorder characterized by smooth cerebral surface, thick cortex and dilated lateral ventricules due to defective neuronal migration. Lis1 was identified as a mutated gene in classical lissencephaly patients, and turned out to be a beta-subunit of platelet activating factor acetylhydrolase. Studies in model organisms, particularly Aspergillus nidulans, as well as those in the mouse, have uncovered an evolutionarily conserved pathway that involves LIS1 and cytoplasmic dynein. LIS1 was subsequently found to associate physically with two NudE orthologs, Ndel and its isoform Ndell. These observations also strengthen that LIS1 gene has been implicated in regulating cytoplasmic dynein. Lis1+/- neurons displayed increased and more variable separation between the nucleus and the preceding centrosome during migration. Dynein inhibition resulted in similar defects in both nucleus-centrosome (N-C) coupling and neuronal migration, suggesting that defects in this coupling may contribute to migration defects in lissencephaly. Recent report suggests that LIS1 also plays an important role on the determination cleavage plane of neuronal progenitor cells. Controlled gene deletion of Lis1 in vivo in neuroepithelial stem cells, where cleavage is uniformly vertical and symmetrical, provokes rapid apoptosis of those cells. Ndell is also involved in the regulation of microtubule organization, and becomes the target of various kinases and phosphatases, including CDK5/CDK1, Aurora-A and PP4. Coordinated regulation of cytoplasmic dynein and microtubule organization is vital for proper cell division and cell positioning, which is an important research problem for understanding of corticogenesis and promoting the development of new therapies for lissencephaly and related disorders.
Hirotsune
Shinji
S
Department of Medical Science, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D054082:Lissencephaly / Q000235:genetics*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000502:physiology
D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C421108:NDEL1 protein, human; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D004398:Dyneins