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Maintenance de la stabilité chromosomique des cellules souches neurales murines au cours du développement et après un stress génotoxique aiguë ou chronique

Abstract : Prenatal exposure to ionizing radiation has been associated with many neurodevelopmental disorders due to the DNA damage induced in neural stem and progenitors cells (NSPC). Thus, genetic stability of NSPC is crucial for brain development and homeostasis. Nevertheless, genomic alterations occurring during development in NSPC may have a potential impact on the physiological neuronal diversity. XLF is a component of the NHEJ (Non-Homologous End-Joining) repair pathway. Here, we show that NSPC from Xlf-/- embryos exhibit increased chromosome instability, leading to premature neurogenesis and consequently neurobehavioral disorders. Using cytogenetic approaches, we compared the chromosome stability of mouse embryonic NSPC and fibroblasts (MEF) exposed to acute (γ-irradiation) or chronic (incorporation of tritiated thymidine into DNA) genotoxic stress. Our results demonstrate the higher capacity of NSPC as compared to MEF to maintain their genomic integrity. We evidenced that NSPC have more efficient DNA repair activity than MEF, allowing them to develop an adaptive response to chronic genotoxic stress. This adaptive response involves XLF and acts together with apoptosis and cell cycle checkpoints to preserve the stability of the genome and to eliminate damaged cells. Altogether, our results provide new insights into the robust DNA damage response in NSPC and highlight the importance of Xlf during brain development.
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Submitted on : Thursday, August 20, 2020 - 3:19:08 PM
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Sofiane Mokrani. Maintenance de la stabilité chromosomique des cellules souches neurales murines au cours du développement et après un stress génotoxique aiguë ou chronique. Neurosciences. Institut Polytechnique de Paris, 2019. Français. ⟨NNT : 2019IPPAX010⟩. ⟨tel-02918458⟩

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