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Human Molecular Genetics Advance Access originally published online on March 28, 2006
Human Molecular Genetics 2006 15(9):1387-1400; doi:10.1093/hmg/ddl062
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Branching and nucleokinesis defects in migrating interneurons derived from doublecortin knockout mice

Caroline Kappeler1,3,4,5, Yoann Saillour1,3,4,5,{dagger}, Jean-Pierre Baudoin6,{dagger}, Françoise Phan Dinh Tuy1,3,4,5, Chantal Alvarez6, Christophe Houbron2,3,4,5, Patricia Gaspar6, Ghislaine Hamard2,3,4,5, Jamel Chelly1,3,4,5, Christine Métin3 and Fiona Francis1,3,4,5,*

1Département de Génétique et Développement and 2Homologous Recombination Laboratory, Institut Cochin, F-75014 Paris, France, 3INSERM U567, Paris, France, 4CNRS UMR 8104, Paris, France, 5Université Paris 5, Faculté de Médecine René Descartes, UM 3, 75014 Paris, France and 6U616 INSERM, Hôpital Pitié-Salpêtrière, 47, Bld de l'Hôpital, 75651 Paris Cédex 13, France

* To whom correspondence should be addressed at: Institut Cochin, Faculté de Médecine Cochin Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France. Tel: +33 144412429; Fax: +33 144412421; Email: francis{at}cochin.inserm.fr

Received January 4, 2006; Accepted March 10, 2006

Type I lissencephaly results from mutations in the doublecortin (DCX) and LIS1 genes. We generated Dcx knockout mice to further understand the pathophysiological mechanisms associated with this cortical malformation. Dcx is expressed in migrating interneurons in developing human and mouse brains. Video microscopy analyses of such tangentially migrating neuron populations derived from the medial ganglionic eminence show defects in migratory dynamics. Specifically, the formation and division of growth cones, leading to the production of new branches, are more frequent in knockout cells, although branches are less stable. Dcx-deficient cells thus migrate in a disorganized manner, extending and retracting short branches and making less long-distant movements of the nucleus. Despite these differences, migratory speeds and distances remain similar to wild-type cells. These novel data thus highlight a role for Dcx, a microtubule-associated protein enriched at the leading edge in the branching and nucleokinesis of migrating interneurons.

{dagger}These authors contributed equally.


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