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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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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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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