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The Journal of Neuroscience, April 4, 2007, 27(14):3875-3883; doi:10.1523/JNEUROSCI.4530-06.2007

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Cellular/Molecular
Both Doublecortin and Doublecortin-Like Kinase Play a Role in Cortical Interneuron Migration

Gaëlle Friocourt,¹ Judy S. Liu,² Mary Antypa,¹ Sonja Raki,¹ Christopher A. Walsh,² and John G. Parnavelas¹

¹Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, and ²Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Division of Genetics, Children's Hospital and Department of Neurology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

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

Type I lissencephaly, a genetic disease characterized by disorganized cortical layers and gyral abnormalities, is associated with severe cognitive impairment and epilepsy. Two genes, LIS1 and doublecortin (DCX), have been shown to be responsible for a large proportion of cases of type I lissencephaly. Both genes encode microtubule-associated proteins that have been shown to be important for radial migration of cortical pyramidal neurons. To investigate whether DCX also plays a role in cortical interneuron migration, we inactivated DCX in the ganglionic eminence of rat embryonic day 17 brain slices using short hairpin RNA. We found that, when DCX expression was blocked, the migration of interneurons from the ganglionic eminence to the cerebral cortex was slowed but not absent, similar to what had previously been reported for radial neuronal migration. In addition, the processes of DCX-deficient migrating interneurons were more branched than their counterparts in control experiments. These effects were rescued by DCX overexpression, confirming the specificity to DCX inactivation. A similar delay in interneuron migration was observed when Doublecortin-like kinase (DCLK), a microtubule-associated protein related to DCX, was inactivated, although the morphology of the cells was not affected. The importance of these genes in interneuron migration was confirmed by our finding that the cortices of Dcx, Dclk, and Dcx/Dclk mutant mice contained a reduced number of such cells in the cortex and their distribution was different compared with wild-type controls. However, the defect was different for each group of mutant animals, suggesting that DCX and DCLK have distinct roles in cortical interneuron migration.

Key words: interneurons; DCX; DCLK; lissencephaly; tangential migration; RNAi

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Received Oct. 18, 2006; revised Feb. 11, 2007; accepted March 5, 2007.

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

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				G. Friocourt, S. Kanatani, H. Tabata, M. Yozu, T. Takahashi, M. Antypa, O. Raguenes, J. Chelly, C. Ferec, K. Nakajima, et al. Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis J. Neurosci., May 28, 2008; 28(22): 5794 - 5805. [Abstract] [Full Text] [PDF]

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