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

• Type of Material: Article
• 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
• Language: English
• Date: 2004-06-07
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2004, The Rockefeller University Press
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1083/jcb.200309025
• Title of Journal or Parent Work: Journal of Cell Biology
• ISSN: 0021-9525
• Volume: 165
• Issue: 5
• Start Page: 709
• End Page: 721
• Grant/Funding Information: This work was supported by a Post-doctoral Research Training Fellowship (T. Tanaka) and the Junior Investigator Research Grant from the Epilepsy Foundation of America, by the National Institute of Neurological Disorders and Stroke (K12NS01701, R01 NS41537), the University of California, San Diego Neuroscience Microscopy Shared Facility (NS047101), the John Merck Award in the Developmental Disabilities in Childhood, the Searle Scholars Program, and the Klingenstein Foundation.
• Keywords: CEREBELLAR GRANULE NEURONS; Lis 1; doublecortin; CEREBRAL-CORTEX; Science & Technology; VARIABLE PHENOTYPES; migration; centrosome; CYTOPLASMIC DYNEIN; ASPERGILLUS-NIDULANS; CORTICAL DEVELOPMENT; nucleus; MICROTUBULE-ASSOCIATED PROTEIN; MISSENSE MUTATIONS; Life Sciences & Biomedicine; Cell Biology; SUBCORTICAL BAND HETEROTOPIA; DOUBLE CORTEX SYNDROME
• Research Categories: Biology, Neuroscience; Health Sciences, Human Development

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.