TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis

0505195 - ÚMG 2020 RIV GB eng J - Článek v odborném periodiku
Ivanova, E.L. - Gilet, J.G. - Sulimenko, Vadym - Duchon, A. - Rudolf, G. - Runge, K. - Collins s, S.C. - Asselin, L. - Broix, L. - Drouot, N. - Tiiiy, P. - Nusbaum, P. - Vincent, A. - Magnant, W. - Skory, V. - Birling, M.C. - Pavlovic, G. - Godin, J.D. - Yalcin, B. - Herault, Y. - Dráber, Pavel - Chelly, J. - Hinckelmann, M.V.
TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.
Nature Communications. Roč. 10, č. 1 (2019), č. článku 2129. E-ISSN 2041-1723
Grant CEP: GA ČR GA16-23702S; GA ČR(CZ) GA18-27197S
Institucionální podpora: RVO:68378050
Klíčová slova: developing mouse-brain * tubulin small complex * spindle pole body * gamma-tubulin * centrosomal protein * animal-models * mutations * mice * migration * gene
Obor OECD: Cell biology
Impakt faktor: 12.121, rok: 2019
Způsob publikování: Open access
https://www.nature.com/articles/s41467-019-10081-8

De novo heterozygous missense variants in the gamma-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(Y)(92)(C/+) mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1(Y)(92)(C/+) animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1(Y)(92)(C/+) mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
Trvalý link: http://hdl.handle.net/11104/0296694