EFHC1 interacts with microtubules to regulate cell division and cortical development.
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.
de Nijs
Laurence
L
GIGA-Neurosciences, University of Liège, Liège, Belgium.
Léon
Christine
C
Nguyen
Laurent
L
Loturco
Joseph J
JJ
Delgado-Escueta
Antonio V
AV
Grisar
Thierry
T
Lakaye
Bernard
B
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D011485:Protein Binding; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection / Q000379:methods
D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins