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

• Published in: Nature communications Vol. 10; no. 1; pp. 2129 - 110
• Main Authors: Ivanova, Ekaterina L., Gilet, Johan G., Sulimenko, Vadym, Duchon, Arnaud, Rudolf, Gabrielle, Runge, Karen, Collins, Stephan C., Asselin, Laure, Broix, Loic, Drouot, Nathalie, Tilly, Peggy, Nusbaum, Patrick, Vincent, Alexandre, Magnant, William, Skory, Valerie, Birling, Marie-Christine, Pavlovic, Guillaume, Godin, Juliette D., Yalcin, Binnaz, Hérault, Yann, Dráber, Pavel, Chelly, Jamel, Hinckelmann, Maria-Victoria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/44; 13/51; 14/1; 14/19; 14/28; 14/35; 38/22; 38/23; 38/88; 38/91; 45; 631/136; 631/136/1425; 631/136/368; 631/378; 631/378/2571; 64; 64/110; 64/60; 82/1; 82/80; 82/83; Anatomy; Animals; Behavior, Animal; Cell Movement - genetics; Centrosome - metabolism; Cerebral Cortex - abnormalities; Cerebral Cortex - cytology; Cerebral Cortex - diagnostic imaging; Cortex; Defects; Disease Models, Animal; Disruption; Electroporation; Embryo, Mammalian; Epilepsy; Epilepsy - genetics; Female; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Fibroblasts - ultrastructure; Gene Knock-In Techniques; Genetic Predisposition to Disease; Genetics; HeLa Cells; Human health and pathology; Humanities and Social Sciences; Humans; Intravital Microscopy; Life Sciences; Locomotion; Male; Malformations of Cortical Development - genetics; Mice; Mice, Transgenic; Microscopy, Confocal; Microscopy, Electron; Microtubules - genetics; Microtubules - metabolism; multidisciplinary; Mutation; Mutation, Missense; Neural stem cells; Neurogenesis; Neurogenesis - genetics; Neurons; Neurons - physiology; Phenotypes; Science; Science (multidisciplinary); Structure-function relationships; Tubulin; Tubulin - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10081-8

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 Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1 Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1 Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations. New mutations and genes associated with malformations of cortical development keep being identified, yet there is little known about the underlying cellular mechanisms controlling these impairments. Here, authors generate and characterize a heterozygous TUBG1 knock-in mouse model bearing one of these known mutations and show that TUBG1 mutation leads to the miss-positioning of neurons in the cortical wall due to migration, because of defective microtubules dynamics, and not proliferation defects during corticogenesis.