Abstract
Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report α2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppression of α2-chimaerin arrested neuronal migration at the multipolar stage, leading to accumulation of ectopic neurons in the subcortical region. Mice with such migration defects showed an imbalance between excitation and inhibition in local cortical circuitry and greater susceptibility to convulsant-induced seizures. We further show that α2-chimaerin regulates bipolar transition and neuronal migration through modulating the activity of CRMP-2, a microtubule-associated protein. These findings establish a new α2-chimaerin-dependent mechanism underlying neuronal migration and proper functioning of the cerebral cortex and provide insights into the pathogenesis of seizure-related neurodevelopmental disorders.
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Acknowledgements
We are grateful to C. Hall (University College London) for α2-chimaerin constructs, antibody and CRMP-2 constructs; K. Kaibuchi (Nagoya University Graduate School of Medicine) for pCRMP-2 (Thr514) antibody; and T. Matsuda and C.L. Cepko (Harvard Medical School) for pCAG vectors. We thank N. Brose and T. Marquardt (Max Planck Institute) for providing Chn1−/− mice. We thank K.-O. Lai and Z. Cheung for critical reading of the manuscript and members of the Ip laboratory for discussions. We also thank C. Kwong, H.W. Tsang, Y. Dai, B. Butt, T. Ye and K. Ho for technical assistance. This study was supported in part by the Research Grants Council of Hong Kong (HKUST 661007, 660808, 660610 and 660110), the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01) and the Hong Kong Jockey Club. J.P.K.I. and N.Y.I. are recipients of a Croucher Foundation Research Studentship and Croucher Foundation Senior Research Fellowship, respectively.
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N.Y.I. supervised the project. J.P.K.I., L.S., Y.C., W.-Y.F., A.K.Y.F. and N.Y.I. designed the experiments. J.P.K.I. and L.S. conducted the majority of experiments. J.P.K.I., L.S., Y.C., A.K.Y.F. and N.Y.I. performed the data analyses. Y.I. and Y.G. provided technical support on in utero electroporation and live-imaging experiments. J.P.K.I. and Y.I. performed live-imaging experiments. W.-H.Y. performed the electrophysiology experiments and subsequent data analyses. A.B. provided Chn1−/− mice. J.P.K.I., L.S., A.K.Y.F. and N.Y.I. wrote the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–11 (PDF 1711 kb)
Supplementary Video 1
This movie shows the migration of neurons electroporated with pSUPER vector and GFP plasmids. Most of the neurons attained bipolar shape, underwent nuclear translocation and migrated up to the cortical plate. Images were captured every 15 min for 13 h. (MOV 606 kb)
Supplementary Video 2
This movie shows the migration of neurons electroporated with α2-chimerin shRNA and GFP plasmids. α2-chimerin knockdown neurons were unable to enter into the cortical plate, and showed local movement within the intermediate zone. Images were captured every 15 min for 13 h. (MOV 588 kb)
Supplementary Video 3
This movie shows an example of migrating neurons electroporated with pSUPER vector and GFP plasmids. The neuron extended and retracted neurites actively, and eventually formed one major leading process guiding the migration of cell body towards pial surface. Images were captured every 10 min for 7 h. (MOV 587 kb)
Supplementary Video 4
This movie shows an example of migrating neurons electroporated with α2-chimerin shRNA and GFP plasmids. The neuron showed impaired neurite dynamics and failed to form a leading process towards pial surface. Images were captured every 10 min for 7 h. (MOV 609 kb)
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Ip, J., Shi, L., Chen, Y. et al. α2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2. Nat Neurosci 15, 39–47 (2012). https://doi.org/10.1038/nn.2972
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DOI: https://doi.org/10.1038/nn.2972
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