Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development.
Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. LIS1 was first gene cloned in an organism important for neuronal migration, as it was deleted or mutated in patients with lissencephaly in a heterozygous fashion. 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. This pathway codes for proteins in a complex with cytoplasmic dynein and positively regulates its conserved function in nuclear migration. This complex appears to be important for proliferation and neuronal survival as well as neuronal migration. One of the components of this complex, NDEL1, is a phosphoprotein that is a substrate for CDK5 (or CDK2 in fibroblasts) and Aurora-A, two mitotic kinases. CDK5-phosphorylated NDEL1 binds to 14-3-3epsilon, which protects it from phosphatase attack. Interestingly, 14-3-3epsilon is located 1 Mb from LIS1 and is heterozygously deleted with LIS1 in patients with a severe form of lissencephaly, Miller-Dieker syndrome. Mouse models confirm that 14-3-3epsilon plays an important role in neuronal migration, and mice that are double heterozygotes for mutations in Lis1 and 14-3-3epsilon, display more severe neuronal migration defects. The identification of LIS1 as the first lissencephaly gene, and the first gene required for neuronal migration has revealed the importance of the regulation of cytoplasmic dynein in the control of neuronal migration by modulating nuclear migration in a pathway conserved in virtually all eukaryotes.
Wynshaw-Boris
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Departments of Pediatrics and Medicine, UCSD School of Medicine, University of California-San Diego, La Jolla, CA, USA. awynshawboris@ucsd.edu
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001233:Aspergillus nidulans / Q000378:metabolism; D001921:Brain / Q000002:abnormalities*; D001927:Brain Diseases / Q000235:genetics*; D002465:Cell Movement; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology*; D008954:Models, Biological; D009421:Nervous System Malformations / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human