Premium
[P2.19]: EFHC1, a protein mutated in juvenile myoclonic epilepsy, is involved in cell division and neuronal migration during brain development
Author(s) -
Nijs L.,
Léon C.,
Nguyen L.,
Grisar T.,
Lakaye B.
Publication year - 2010
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2010.07.149
Subject(s) - juvenile myoclonic epilepsy , library science , epilepsy , neuroscience , psychology , computer science
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 called microdysgenesis, but the underlying pathological mechanism remains unknown. EFHC1 is a non-ion channel protein containing three DM10 domains of unknown function and a single EF-hand motif, a Ca2+ binding domain. Our aim is to study the functional properties of EFHC1. We showed that EFHC1 is a unique microtubule-associated protein (MAP) involved in the regulation of cell division in vitro. Moreover, expression of EFHC1 transcript and protein in mouse brain is highest during embryogenesis, when cell divisions are prominent. Collectively, these results suggest a function of EFHC1 during brain development. In order to study the role of EFHC1 during corticogenesis, we modulated its expression (gain and loss of function) in the E17 rat neocortex by ex vivo and in utero electroporations methods. We showed that EFHC1 impairment caused a dramatic disruption of radial migration by affecting different steps of corticogenesis: (i) division, cell cycle exit and survival of cortical progenitors, (ii) organization of radial glia scaffolding and (iii) locomotion of post-mitotic neurons. We have demonstrated for the first time that a gene responsible for an IGE encodes a new MAP that plays a crucial role in the regulation of cell division and neuronal migration during brain development. Accordingly, our findings suggest that microdysgenesis found in patients suffering from JME could partly result from radial neuronal migration defects produced by EFHC1 mutations and that they could lead to abnormal epileptogenic circuitry during cortical maturation at adolescence onset. Therefore, instead of being a new form of “channelopathy”, as it is often the case in IGE, JME could be the expression of certain types of microdysgenesis.