RNAi reveals doublecortin is required for radial migration in rat neocortex (original) (raw)
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- Published: 16 November 2003
Nature Neuroscience volume 6, pages 1277–1283 (2003)Cite this article
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Abstract
Mutations in the doublecortin gene (DCX) in humans cause malformation of the cerebral neocortex. Paradoxically, genetic deletion of Dcx in mice does not cause neocortical malformation. We used electroporation of plasmids encoding short hairpin RNA to create interference (RNAi) of DCX protein in utero, and we show that DCX is required for radial migration in developing rat neocortex. RNAi of DCX causes both cell-autonomous and non-cell autonomous disruptions in radial migration, and creates two disruptions in neocortical development. First, many neurons prematurely stop migrating to form subcortical band heterotopias within the intermediate zone and then white matter. Second, many neurons migrate into inappropriate neocortical lamina within normotopic cortex. In utero RNAi can therefore be effectively used to study the specific cellular roles of DCX in neocortical development and to produce an animal model of double cortex syndrome.
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References
- Sidman, R.L. & Rakic, P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. 62, 1–35 (1973).
Article CAS Google Scholar - Marin-Padilla, M. The development of the human cerebral cortex. A cytoarchitectonic theory. Rev. Neurol. 29, 208–216 (1999).
CAS PubMed Google Scholar - Gupta, A., Tsai, L.H. & Wynshaw-Boris, A. Life is a journey: a genetic look at neocortical development. Nat. Rev. Genet. 3, 342–355 (2002).
Article CAS Google Scholar - Walsh, C.A. & Goffinet, A.M. Potential mechanisms of mutations that affect neuronal migration in man and mouse. Curr. Opin. Genet. Dev. 10, 270–274 (2000).
Article CAS Google Scholar - Gleeson, J.G., Lin, P.T., Flanagan, L.A. & Walsh, C.A. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23, 257–271 (1999).
Article CAS Google Scholar - Francis, F. et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23, 247–256 (1999).
Article CAS Google Scholar - des Portes, V. et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92, 51–61 (1998).
Article CAS Google Scholar - Gleeson, J.G. et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92, 63–72 (1998).
Article CAS Google Scholar - Kato, M. & Dobyns, W.B. Lissencephaly and the molecular basis of neuronal migration. Hum. Mol. Genet. 12, R89–96 (2003).
Article CAS Google Scholar - Feng, Y. & Walsh, C.A. Protein-protein interactions, cytoskeletal regulation and neuronal migration. Nat. Rev. Neurosci. 2, 408–416 (2001).
Article CAS Google Scholar - Horesh, D. et al. Doublecortin, a stabilizer of microtubules. Hum. Mol. Genet. 8, 1599–1610 (1999).
Article CAS Google Scholar - Corbo, J.C. et al. Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J. Neurosci. 22, 7548–7557 (2002).
Article CAS Google Scholar - Yu, J.Y., DeRuiter, S.L. & Turner, D.L. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc. Natl. Acad. Sci. USA 99, 6047–6052 (2002).
Article CAS Google Scholar - Takahashi, M., Sato, K., Nomura, T. & Osumi, N. Manipulating gene expressions by electroporation in the developing brain of mammalian embryos. Differentiation 70, 155–162 (2002).
Article CAS Google Scholar - Gleeson, J.G. et al. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann. Neurol. 45, 146–153 (1999).
Article CAS Google Scholar - Gleeson, J.G. et al. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am. J. Hum. Genet. 67, 574–581 (2000).
Article CAS Google Scholar - Nadarajah, B., Brunstrom, J.E., Grutzendler, J., Wong, R.O. & Pearlman, A.L. Two modes of radial migration in early development of the cerebral cortex. Nat. Neurosci. 4, 143–150 (2001).
Article CAS Google Scholar - Lois, C., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Chain migration of neuronal precursors. Science 271, 978–981 (1996).
Article CAS Google Scholar - Gleeson, J.G. et al. Genetic and neuroradiological heterogeneity of double cortex syndrome. Ann. Neurol. 47, 265–269 (2000).
Article CAS Google Scholar - Okada, A., Lansford, R., Weimann, J.M., Fraser, S.E. & McConnell, S.K. Imaging cells in the developing nervous system with retrovirus expressing modified green fluorescent protein. Exp. Neurol. 156, 394–406 (1999).
Article CAS Google Scholar - Bittman, K.S. & LoTurco, J.J. Differential regulation of connexin 26 and 43 in murine neocortical precursors. Cereb. Cortex 9, 188–195 (1999).
Article CAS Google Scholar - Gabel, L.A. & LoTurco, J.J. Electrophysiological and morphological characterization of neurons within neocortical ectopias. J. Neurophysiol. 85, 495–505 (2001).
Article CAS Google Scholar
Acknowledgements
R.L.R. and J.B.A. contributed equally to this work. We thank S. Korn, A. Moiseff and M. Paramasivam for helpful discussions and comments on drafts of the manuscript. We also thank D. Turner for the mU6pro vector. This work was supported by the National Institute of Mental Health (MH056524 to J.J.L.) and the National Institute of Child Health and Human Development (HD20806).
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Authors and Affiliations
- Department of Physiology and Neurobiology, University of Connecticut, 3107 Horsebarn Hill Road, U-4156, Storrs, Connecticut, 06269, USA
Jilin Bai, Raddy L Ramos, James B Ackman, Ankur M Thomas, Richard V Lee & Joseph J LoTurco
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- Jilin Bai
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Correspondence toJoseph J LoTurco.
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Bai, J., Ramos, R., Ackman, J. et al. RNAi reveals doublecortin is required for radial migration in rat neocortex.Nat Neurosci 6, 1277–1283 (2003). https://doi.org/10.1038/nn1153
- Received: 27 August 2003
- Accepted: 21 October 2003
- Published: 16 November 2003
- Issue Date: 01 December 2003
- DOI: https://doi.org/10.1038/nn1153