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A novel role for CAMKIIβ in the regulation of cortical neuron migration: implications for neurodevelopmental disorders

Molecular Psychiatry volume 23, pages 2209–2226 (2018)Cite this article

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Abstract

Perturbation of CaMKIIβ expression has been associated with multiple neuropsychiatric diseases, highlighting CaMKIIβ as a gene of interest. Yet, in contrast to CaMKIIα, the specific functions of CaMKIIβ in the brain remain poorly explored. Here, we reveal a novel function for this CaMKII isoform in vivo during neuronal development. By using in utero electroporation, we show that CaMKIIβ is an important regulator of radial migration of projection neurons during cerebral cortex development. Knockdown of CaMKIIβ causes accelerated migration of nascent pyramidal neurons, whereas overexpression of CaMKIIβ inhibits migration, demonstrating that precise regulation of CaMKIIβ expression is required for correct neuronal migration. More precisely, CaMKIIβ controls the multipolar–bipolar transition in the intermediate zone and locomotion in the cortical plate through its actin-binding and -bundling activities. In addition, our data indicate that a fine-tuned balance between CaMKIIβ and cofilin activities is necessary to ensure proper migration of cortical neurons. Thus, our findings define a novel isoform-specific function for CaMKIIβ, demonstrating that CaMKIIβ has a major biological function in the developing brain.

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Acknowledgements

We thank Dr. Paul de Koninck for providing CaMKIIβ, Dr. Azad Bonni for providing CaMKIIβ-ΔFABD, CaMKIIβ-Δasso, CaMKIIβ-K43R and CaMKIIβ-ΔCTS constructs, Dr. Yasunori Hayashi for providing CaMKIIβ-All A and CaMKIIβ-All D. We are also grateful to Drs. Iryna Ethell, Mary Hatten, Mathieu Vermeren and Franck Oury for providing the constructs expressing wild-type or mutated forms of cofilin, pCIG2-Centrin2-Venus, pCA-b-EGFPm5 silencer 3 and the RNA sens and antisense probes for CaMKIIβ, respectively. We gratefully acknowledge Dr. Roberta Azzarelli for comments on the manuscript. Image analysis was partially done in the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging. This work benefited from the support of the Transcriptomic facility funded by INSERM and LabEX BRAIN ANR-10-LABX-43 and was supported by INSERM, CNRS, Bordeaux University, Marie Curie Actions (Intra European Fellowship), FRM (grant DEQ20130326468) and institutional funds from the Medical Research Council to F.G.

Author contributions

E.P. and O.N. designed and carried out experiments. E.P. wrote the manuscript. D.M.B. and F.G helped with live imaging experiments. T.L.-L. and H.D. performed PCR analyses. All authors discussed results from experiments and commented on the manuscript.

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Authors and Affiliations

  1. CNRS, UMR5293, Institut des Maladies Neurodégénératives, F-33000, Bordeaux, France

    Olivier Nicole

  2. Université de Bordeaux, F-33000, Bordeaux, France

    Olivier Nicole & Emilie Pacary

  3. Confocal and Image Analysis Facility, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK

    Donald M. Bell

  4. Transcriptome Facility, INSERM U1215, Neurocentre Magendie, F-33000, Bordeaux, France

    Thierry Leste-Lasserre & Hélène Doat

  5. The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK

    François Guillemot

  6. INSERM U1215, Neurocentre Magendie, F-33000, Bordeaux, France

    Emilie Pacary

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  1. Olivier Nicole
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Correspondence to Emilie Pacary.

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Nicole, O., Bell, D.M., Leste-Lasserre, T. et al. A novel role for CAMKIIβ in the regulation of cortical neuron migration: implications for neurodevelopmental disorders. Mol Psychiatry 23, 2209–2226 (2018). https://doi.org/10.1038/s41380-018-0046-0

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