期刊
JOURNAL OF CELL BIOLOGY
卷 165, 期 5, 页码 709-721出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200309025
关键词
migration; Lis 1; doublecortin; centrosome; nucleus
类别
资金
- NINDS NIH HHS [K12 NS001701, R01 NS41537, P30 NS047101, K12NS01701, R01 NS041537, NS047101] Funding Source: Medline
Humans with mutations in either DCX or LIS1 display nearly identical neuronal migration defects, known as lissencephaly. To define subcellular mechanisms, we have combined in vitro neuronal migration assays with retroviral transduction. Overexpression of wild-type Dcx or Lis1, but not patient-related mutant versions, increased migration rates. Dcx overexpression rescued the migration defect in Lis1(+/-) neurons. Lis1 localized predominantly to the centrosome, and after disruption of microtubules, redistributed to the perinuclear region. Dcx outlined microtubules extending from the perinuclear cage to the centrosome. 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. These N-C coupling defects were rescued by Dcx overexpression, and Dcx was found to complex with dynein. These data indicate Lis1 and Dcx function with dynein to mediate N-C coupling during migration, and suggest defects in this coupling may contribute to migration defects in lissencephaly.
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