期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10081-8
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资金
- EU Seventh Framework Programme FP7 under the project GENCODYS [2009-2.1.1-1/241995]
- EU Seventh Framework Programme FP7 under the project DESIRE [602531]
- French state funds through the Agence Nationale de la Recherche [ANR-15-CE16-0018-01]
- programme Investissements d'Avenir labelled [ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN]
- Grant Agency of the Czech Republic [16-23702s, 18-27197s]
- [RVO 68378050]
- Agence Nationale de la Recherche (ANR) [ANR-15-CE16-0018] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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