EFHC1 interacts with microtubules to regulate cell division and cortical development

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.

Distribution of EFHC1 or Myoclonin 1 in mouse neural structures

“…A significant, although faint, labeling was also observed in neocortex and piriform cortex. We have confirmed that in our recently published paper showing the expression of EFHC1 protein in E17 rat cortex (de Nijs et al, 2009). The poor expression of the signal in general does not allow a quantitative comparison with what has been observed in adulthood, although it is evident that the best pictures of nerve structures have been obtained with adult animals.…”

“…Taken together, our previous (de Nijs et al, , 2009) and present results strongly suggest a particular function for EFHC1 in the central nervous system development. During ontogenesis of the cerebral cortex, neuronal progenitors are generated in the ventricular zone by a specialized and transient class of glial cells, the radial glial cells.…”

“…Since we have previously suggested a possible role of EFHC1 in cell division and brain development Grisar et al, 2006) and recently confirmed that this molecule is a MAP implicated in neuronal migration (de Nijs et al, 2009), it was important, in front of these controversial initial data, to check the presence of this transcript and protein in some nerve cells in culture as well as in brain structures both in adulthood and during development.…”

“…These results suggest that EFHC1 could play an important role during cell division and in particular during brain development since mRNA expression is higher at embryonic stages as compared to adult . We very recently demonstrated that in fact EFHC1 is a microtubule-associated protein (MAP) playing a key role in neuronal migration (de Nijs et al, 2009). Some recent studies however showed a restricted localization of the protein at the ependymal epithelium Conte et al, 2009) questioning its expression in brain tissue, neuronal or glial cells.…”

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

“…Five EFHC1 variants were originally reported in JME patients from Mexico 16 (P77T, D210N, R221H, F229L, and D253Y), in reverse TRPM2-induced (transient receptor potential calcium permeable M2 channel) apoptosis, and in current densities. 57 Four of these variants (the exception was P77T, which was not tested) produce severe mitotic spindle defects during cell division 55 and impair early radial and tangential migration of neuroblasts, 56 thus providing experimental evidence that EFHC1 variants are damaging to gene function. Supplementary Table S6a,b online show the published statistical results of 14 experimental measures demonstrating a significant difference between the tested variants and the wild-type protein.…”