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Physiopathologie des malformations du développement cortical associées à des mutations du gène tubuline β3

Abstract : Over the last years, the critical role of the cytoskeletal network in the proper cortical development has been established. The importance of microtubules was further emphasized with the association of mutations in gene encoding for alpha-tubulin (TUBA1A, TUBA8), beta-tubulin (TUBB2B) in malformations of cortical development (MCD) including lissencephalies and polymicrogyria (Keays 2007, Poirier 2007, Jaglin 2009, Abdollahi 2009) and TUBB5 in microcephaly with cortical gyration abnormalities. We report the implication of TUBB3 missense mutations in polymicrogyria and cortical simplifications in 6 different families including a foetal case harboring a severe micerolissencephaly.We investigated the properties of MT network in patients' fibroblasts and revealed that MCD-related mutations can alter the resistance of microtubules to depolymerisation. These results led us to hypothesise that either microtubule dynamics or their interactions with various MT interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum. In a second time, we investigate further the association between TUBB3 mutations and MCDs by analyzing the consequences of Tubb3 knockdown on cortical development in mice. Using the in utero electroporation approach, we demonstrate that Tubb3 knockdown leads to delayed bipolar morphology and radial migration with evidence suggesting that the neuronal arrest is a transient phenomenon overcome after birth. Silenced blocked cells display a round shape and decreased number of processes and a delay in the acquisition of the bipolar morphology. Also, more Tbr2 positive cells are observed, although less cells express the proliferation marker Ki67, suggesting that Tubb3 inactivation might have an indirect effect on intermediate progenitor proliferation. Furthermore, we show by rescue experiments the non interchangeability of other beta-tubulins which are unable to rescue the phenotype. Our study highlights the critical and specific role of Tubb3 on the stereotyped morphological changes and polarization processes that are required for initiating radial migration to the cortical plate.
Keywords : Neurosciences
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Submitted on : Tuesday, December 17, 2013 - 12:08:15 PM
Last modification on : Friday, December 2, 2022 - 4:15:40 PM
Long-term archiving on: : Monday, March 17, 2014 - 11:00:40 PM


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  • HAL Id : tel-00919773, version 1



Yoann Saillour. Physiopathologie des malformations du développement cortical associées à des mutations du gène tubuline β3. Médecine humaine et pathologie. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05T035⟩. ⟨tel-00919773⟩



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