Effets cellulaires et moléculaires de l’invalidation conditionnelle du gène MTR au niveau du foie et du cerveau de souris

Abstract : The enzyme methionine synthase (MTR) catalyzes the remethylation of homocysteine to methionine, the precursor of the methyl donor S-universal Adenosylmethionine (SAM), involved in epigenetic regulation mechanisms. We generated mouse models with conditional invalidation of the mtr gene in a constitutive or inducible manner to delete the gene expression specifically in the liver and brain. Constitutive invalidation during embryonic life is not sustainable when targeted to the liver, suggesting a limiting role of methionine synthase in early organogenesis and probably on cell proliferation. We performed hepatectomy to study regeneration-related effects on the cellular stress and found dramatic effects on cell proliferation through altered expression and activation of cyclins. The constitutive model in brain highlighted the behavioral anomalies related to a loss of learning and memory. This suggested major effects in the hippocampus. Overall, our findings highlighted the specific effects of the invalidation of methionine synthase in both organs. The liver is a plastic member with a very high regenerative capacity. The effects on organogenesis and inhibition of regeneration confirm the hypothesis for a major role of methionine synthase in cell cycle regulation. The invalidation model in the brain confirms the important role of the remethylation pathway catalysed by methionine synthase, a role which has been shown by other studies in rats deprived in methyl donors and in cd320 KO transgenic mice
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Peng Lu. Effets cellulaires et moléculaires de l’invalidation conditionnelle du gène MTR au niveau du foie et du cerveau de souris. Sciences du Vivant [q-bio]. Université de Lorraine, 2016. Français. ⟨NNT : 2016LORR0333⟩. ⟨tel-02167327⟩

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