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The Journal of Neuroscience, May 28, 2008, 28(22):5794-5805; doi:10.1523/JNEUROSCI.1067-08.2008

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Cellular/Molecular
Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Gaëlle Friocourt,^{1,8,9,10,11 *} Shigeaki Kanatani,^2 * Hidenori Tabata,² Masato Yozu,² Takao Takahashi,³ Mary Antypa,¹ Odile Raguénès,^8,9,10,11 Jamel Chelly,^5,6,7 Claude Férec,^8,9,10,11 Kazunori Nakajima,^2,4 and John G. Parnavelas¹

¹Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, Departments of ²Anatomy and ³Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan, ⁴Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan, ⁵Institut Cochin, U567, Inserm, ⁶Unité Mixte de Recherche 8104, Centre National de la Recherche Scientifique, ⁷Université Paris Descartes, Paris F-75014, France, ⁸U613, Inserm, ⁹Université Brest, ¹⁰Etablissement Français du Sang Bretagne, and ¹¹Laboratoire de Génétique Moléculaire, Hôpital Morvan, Centre Hospitalier Universitaire de Brest, Brest F-29200, France

Correspondence should be addressed to John G. Parnavelas, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: j.parnavelas{at}ucl.ac.uk

The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interference-mediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.

Key words: ARX; lissencephaly; neuronal migration; RNA interference; interneuron; cell cycle

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Received Nov. 14, 2007; accepted April 16, 2008.

Correspondence should be addressed to John G. Parnavelas, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: j.parnavelas{at}ucl.ac.uk

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