Role of the ciliogenic transcription factor RFX3 in the lung development in mice

La protéine RFX3 appartient à une famille de facteurs de transcription RFX (Regulatory Factor X) très conservée au cours de l'évolution. Avec plusieurs autres membres de cette famille, RFX3 est impliquée dans la régulation de l'expression de gènes nécessaires pour l'assemblage et la fonction des cils. L’objectif de mon travail de thèse a été de comprendre le rôle du facteur de transcription RFX3 au cours du développement du poumon de la souris. RFX3 est exprimée dès le début du développement pulmonaire dans les cellules du mésenchyme et de l'épithélium, de manière corrélée à la présence de cils primaires. En absence de RFX3, le nombre des cils primaires est réduit. A la naissance, l’expression de RFX3 se restreint aux cellules multiciliées de l'épithélium bronchique. Les poumons de souris Rfx3-/- ou conditionnellement inactivées pour Rfx3 dans le mésenchyme, présentent un défaut de formation des alvéoles, associé à un nombre réduit de précurseurs des myofibroblastes en cours de migration en périphérie des poumons. In vivo, le nombre de précurseurs des myofibroblastes chez les souris Rfx3-/- est diminué. En culture primaire, les myofibroblastes Rfx3-/- ont une capacité proliférative réduite, ainsi qu'une altération du comportement migratoire. La voie induite par le PDGFAA, facteur de croissance responsable de la migration des myofibroblastes in vivo, est intact chez les myofibroblastes Rfx3-/-. En conclusion, RFX3 régule la croissance des cils primaires et gouverne la différentiation des myofibroblastes pendant le développement du poumon. Ce travail de thèse suggère donc une nouvelle fonction des cils primaires durant le développement pulmonaireRFX3 belongs to the regulatory factor X (RFX) family transcription factors that are conserved in a wide range of species. With several other members of this family, RFX3 is involved in regulating the expression of genes required for assembly and function of cilia. The aim of my thesis was to understand the role of the transcription factor RFX3 during mouse lung development. RFX3 is expressed early in lung development in mesenchymal and epithelial cells, correlated to the presence of primary cilia. In the absence of RFX3, the number of primary cilia is reduced. At birth, RFX3 expression is restricted to multiciliated cells of the bronchial epithelium. The lungs of Rfx3-/- mice, or conditionally inactivated for Rfx3 in the mesenchyme, exhibit an alveolarization defect, associated with a reduced number of myofibroblast precursors that migrate in the lung periphery. In vivo, the number of myofibroblast precursors in Rfx3-/- mice is reduced. In primary culture, Rfx3-/- myofibroblasts have a reduced proliferative capacity, and an altered migratory behavior. The pathway induced by PDGFAA, a growth factor responsible for the myofibroblast migration in vivo, is intact in Rfx3-/- myofibroblasts. In conclusion, RFX3 regulates the growth of primary cilia and governs the differentiation of myofibroblasts during lung development. This thesis suggests a novel function of primary cilia during lung developmen

Epithelial Splicing Regulatory Protein 1 (ESRP1) is a new regulator of stomach smooth muscle development and plasticity

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LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity

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Homodimerization of RBPMS2 through a new RRM-interaction motif is necessary to control smooth muscle plasticity

International audienceIn vertebrates, smooth muscle cells (SMCs) can reversibly switch between contractile and prolifer-ative phenotypes. This involves various molecular mechanisms to reactivate developmental signal-ing pathways and induce cell dedifferentiation. The protein RBPMS2 regulates early development and plasticity of digestive SMCs by inhibiting the bone morphogenetic protein pathway through its interaction with NOGGIN mRNA. RBPMS2 contains only one RNA recognition motif (RRM) while this motif is often repeated in tandem or associated with other functional domains in RRM-containing proteins. Herein, we show using an extensive combination of structure/function analyses that RBPMS2 homodimerizes through a particular sequence motif (D-x-K-x-RE -L-Y-L-L-F: residues 39-51) located in its RRM domain. We also show that this specific motif is conserved among its homologs and par-alogs in vertebrates and in its insect and worm or-thologs (CPO and MEC-8, respectively) suggesting a conserved molecular mechanism of action. Inhibition of the dimerization process through targeting a conserved leucine inside of this motif abolishes the capacity of RBPMS2 to interact with the trans-lational elongation eEF2 protein, to upregulate NOG-GIN mRNA in vivo and to drive SMC dedifferentiation. Our study demonstrates that RBPMS2 possesses an RRM domain harboring both RNA-binding and protein-binding properties and that the newly identified RRM-homodimerization motif is crucial for the function of RBPMS2 at the cell and tissue levels

Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry

International audienceAbstract Aims There has been an increasing focus on integrated, multidisciplinary, and holistic care in the treatment of atrial fibrillation (AF). The ‘Atrial Fibrillation Better Care’ (ABC) pathway has been proposed to streamline integrated care in AF. We evaluated the impact on outcomes of an ABC adherent management in a contemporary real-life European-wide AF cohort. Methods and results Patients enrolled in the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry with baseline data to evaluate ABC criteria and available follow-up data were considered for this analysis. Among the original 11 096 AF patients enrolled, 6646 (59.9%) were included in this analysis, of which 1996 (30.0%) managed as ABC adherent. Patients adherent to ABC care had lower CHA2DS2-VASc and HAS-BLED scores (mean ± SD, 2.68 ± 1.57 vs. 3.07 ± 1.90 and 1.26 ± 0.93 vs. 1.58 ± 1.12, respectively; P < 0.001). At 1-year follow-up, patients managed adherent to ABC pathway compared to non-adherent ones had a lower rate of any thromboembolic event (TE)/acute coronary syndrome (ACS)/cardiovascular (CV) death (3.8% vs. 7.6%), CV death (1.9% vs. 4.8%), and all-cause death (3.0% vs. 6.4%) (all P < 0.0001). On Cox multivariable regression analysis, ABC adherent care showed an association with a lower risk of any TE/ACS/CV death [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44–0.79], CV death (HR: 0.52, 95% CI: 0.35–0.78), and all-cause death (HR: 0.57, 95% CI: 0.43–0.78). Conclusion In a large contemporary cohort of European AF patients, a clinical management adherent to ABC pathway for integrated care is associated with a significant lower risk for cardiovascular events, CV death, and all-cause death