TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.
Fiche publication
Date publication
mai 2019
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Ivanova EL, Gilet JG, Sulimenko V, Duchon A, Rudolf G, Runge K, Collins SC, Asselin L, Broix L, Drouot N, Tilly P, Nusbaum P, Vincent A, Magnant W, Skory V, Birling MC, Pavlovic G, Godin JD, Yalcin B, Hérault Y, Dráber P, Chelly J, Hinckelmann MV
Lien Pubmed
Résumé
De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1 mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1 animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1 mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
Référence
Nat Commun. 2019 05 13;10(1):2129