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Interactions des microARN de la famille miR-34/449 avec les voies de signalisation intracellulaire : rôle dans la différenciation des cellules multiciliées chez les vertébrés

Abstract : Vertebrate multiciliated cells (MCC) project hundreds of motile cilia at their apical surface which coordinately beat to generate a directional fluid flow necessary for many biological functions including airway cleansing. Biogenesis of multiple cilia (multiciliogenesis) follows different key cellular steps corresponding to a cell cycle arrest, a massive multiplication of centrioles which then migrate to the apical surface to form basal bodies, from which cilia elongate. In 2011, my host laboratory evidenced that the miR-34/449 family of microRNAs control vertebrate multiciliogenesis by inducing the cell cycle arrest and by repressing the Notch pathway. My thesis work has revealed a new role of miR-34/449 by demonstrating that they modulate expression and activity of small GTPases to drive the apical reorganization of the actin network, a prerequisite for basal body anchoring. Besides, I have identified and characterized variant sequences of canonical miR-34/449 family, named isomiRs. Whereas these isomiRs share common biological functions with canonical miR-34/449 miRNAs, they may also contribute to a complementary effect by targeting specific transcripts. Finally, the last part of my work has contributed to the identification of the conserved role of the BMP pathway in the control of multiciliogenesis. I have evidenced some molecular mechanisms by which the BMP signal controls this phenomenon. Importantly, I demonstrated that BMP inhibition promotes regeneration of tracheal MCC in vivo in an asthmatic mouse model. Overall, our findings offer an unprecedented opportunity to develop novel therapeutic strategies to treat diseases associated with ciliary disorders
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Submitted on : Sunday, December 3, 2017 - 11:44:19 PM
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Olivier Mercey. Interactions des microARN de la famille miR-34/449 avec les voies de signalisation intracellulaire : rôle dans la différenciation des cellules multiciliées chez les vertébrés. Sciences agricoles. Université Côte d'Azur, 2016. Français. ⟨NNT : 2016AZUR4119⟩. ⟨tel-01654422⟩

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