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EFHC1 interacts with microtubules to regulate cell division and cortical development

Nature Neuroscience volume 12, pages 1266–1274 (2009)Cite this article

Abstract

Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and subcortical architecture, but the underlying pathological mechanism remains unknown. We found that EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. We found that this effect was a result of cortical progenitors failing to exit the cell cycle and defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Therefore, we propose that EFHC1 is a regulator of cell division and neuronal migration during cortical development and that disruption of its functions leads to JME.

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Figure 1: EFHC1 associates with the mitotic spindle through a sequence located in the first 45-amino-acid region.
Figure 2: EFHC1 is a MAP.
Figure 3: EFHC1 is necessary for mitotic spindle organization and M phase progression.
Figure 4: EFHC1 loss of function induces microtubule bundling and apoptosis.
Figure 5: Essential role of EFHC1 in radial neuronal migration.
Figure 6: EFHC1 is crucial for mitosis and cell cycle exit of cortical progenitors.
Figure 7: EFHC1 is implicated in the locomotion of postmitotic neurons.

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Acknowledgements

We thank B. Coumans for skillful technical assistance, J. Bai for help with in utero electroporation processing and S. Ormenese from the GIGA-Imaging and Flow Cytometry platform for support with flow cytometry. We are also grateful to A. Adamantidis for critical reading of the manuscript. We thank F. Polleux for the NeuroD-IRES-GFP plasmid. This work was supported by grants from the F.R.S.-FNRS (Fonds de la Recherche Scientifique Médicale 3.4565.03 to T.G. and B.L.) and the Léon Fredericq Foundation (to L.d.N.). L.N. and B.L. are research associates at the F.R.S.-FNRS.

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Authors and Affiliations

  1. GIGA-Neurosciences, University of Liège, Liège, Belgium

    Laurence de Nijs, Christine Léon, Laurent Nguyen, Thierry Grisar & Bernard Lakaye

  2. Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

    Joseph J LoTurco

  3. David Geffen School of Medicine at University of California Los Angeles, Epilepsy Genetics/Genomics Laboratories, Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California, USA

    Antonio V Delgado-Escueta

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  1. Laurence de Nijs
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Contributions

L.d.N. performed all of the experiments (except for immunoprecipitations), data analysis and wrote the manuscript with help from and editing by all the co-authors. C.L. conducted immunoprecipitations experiments. L.N. helped with the ex vivo and focal electroporation processing. J.J.L. trained L.d.N. for in utero electroporation studies and gave advice as to the interpretation of data. A.V.D.-E. provided plasmids and strong scientific support. T.G. and B.L. were the project leaders. They directed the follow-up of all experiments and supervised the data analysis.

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Correspondence to Thierry Grisar.

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de Nijs, L., Léon, C., Nguyen, L. et al. EFHC1 interacts with microtubules to regulate cell division and cortical development. Nat Neurosci 12, 1266–1274 (2009). https://doi.org/10.1038/nn.2390

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