Cerebral Cortex Advance Access originally published online on August 12, 2008
Cerebral Cortex 2009 19(4):861-875; doi:10.1093/cercor/bhn133
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The p21-Activated Kinase Is Required for Neuronal Migration in the Cerebral Cortex
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1 Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Burlington Dane's Building, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, UK, 2 Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Yoshida-konoecho, Sakyo-ku, Kyoto 606-8501, Japan, 3 Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan, 4 Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan, 5 Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Wako 351-0198, Japan, 6 Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan
Address correspondence to email: m.nikolic{at}imperial.ac.uk.
The normal formation and function of the mammalian cerebral cortex depend on the positioning of its neurones, which occurs in a highly organized, layer-specific manner. The correct morphology and movement of neurones rely on synchronized regulation of their actin filaments and microtubules. The p21-activated kinase (Pak1), a key cytoskeletal regulator, controls neuronal polarization, elaboration of axons and dendrites, and the formation of dendritic spines. However, its in vivo role in the developing nervous system is unclear. We have utilized in utero electroporation into mouse embryo cortices to reveal that both loss and gain of Pak1 function affect radial migration of projection neurones. Overexpression of hyperactivated Pak1 predominantly caused neurones to arrest in the intermediate zone (IZ) with apparently misoriented and disorganized leading projections. Loss of Pak1 disrupted the morphology of migrating neurones, which accumulated in the IZ and deep cortical layers. Unexpectedly, a significant number of neurones with reduced Pak1 expression aberrantly entered into the normally cell-sparse marginal zone, suggesting their inability to cease migrating that may be due to their impaired dissociation from radial glia. Our findings reveal the in vivo importance of temporal and spatial regulation of the Pak1 kinase during key stages of cortical development.
Key Words: cortical development • in utero electroporation • neuronal morphology • Pak1 kinase • radial migration
7 Current address: Institut Jacques Monod, Génétique et développement du cortex cerebral, Tour 43-53, 1er étage 2, Place Jussieu, 75251 Paris, Cedex 05, France
* Frédéric Causeret and Mami Terao have contributed equally to this work.
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