Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration.

• Authors: Teruyuki Tanaka, University of California, San Diego; Finley F. Serneo, University of California, San Diego; Christine Higgins, University of California, San Diego; Michael J. Gambello, Emory University; Anthony Wynshaw-Boris, University of California, San Diego; Joseph G. Gleeson, University of California, San Diego
• Journal Title: Journal of Cell Biology
• Volume: Volume 165, Number 5
• Publisher: Rockefeller University Press | 2004-06-07, Pages 709-721
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1083/jcb.200309025
• Subjects: Biology, Neuroscience; Health Sciences, Human Development
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; migration; Lis 1; doublecortin; centrosome; nucleus; MICROTUBULE-ASSOCIATED PROTEIN; SUBCORTICAL BAND HETEROTOPIA; CEREBELLAR GRANULE NEURONS; DOUBLE CORTEX SYNDROME; CYTOPLASMIC DYNEIN; ASPERGILLUS-NIDULANS; CORTICAL DEVELOPMENT; VARIABLE PHENOTYPES; MISSENSE MUTATIONS; CEREBRAL-CORTEX

Abstract

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.