Conditional switching of KIF2A mutation provides new insights into cortical malformations pathogeny.
Fiche publication
Date publication
janvier 2020
Journal
Human molecular genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHELLY Jamel
Tous les auteurs :
Gilet J, Ivanova E, Trofimova D, Rudolf G, Meziane H, Broix L, Drouot N, Courraud J, Skory V, Voulleminot P, Osipenko M, Bahi-Buisson N, Yalcin B, Birling MC, Hinckelmann MV, Kwok BH, Allingham JS, Chelly J
Lien Pubmed
Résumé
By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model provides, we investigated RosaCre, NestinCre and NexCre driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
Mots clés
in-utero electroporation, KIF2A, apoptosis, cortex, hippocampus, knock-in, malformations of cortical development, microtubule dynamics, mouse model, neuronal migration, videomicroscopy
Référence
Hum. Mol. Genet.. 2020 Jan 10;: