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Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway
Brice Marcet1,2, Benot Chevalier1,2,11, Guillaume Luxardi3,4,11, Christelle Coraux5,6,11, Laure-Emmanuelle Zaragosi1,2, Marie Cibois3,4, Karine Robbe-Sermesant1,2, Thomas Jolly5,6,Bruno Cardinaud1,2,7,8, Chimne Moreilhon1,2,9, Lisa Giovannini-Chami1,2,10, Batrice Nawrocki-Raby5,6, Philippe Birembaut5,6, Rainer Waldmann1,2, Laurent Kodjabachian3,4,12 and Pascal Barbry1,2,12,13
Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing13. However, the mechanisms governing motile cilia biosynthesis remain poorly elucidated. We identify miR-449 microRNAs as evolutionarily conserved key regulators of vertebrate multiciliogenesis. In human airway epithelium and Xenopus laevis embryonic epidermis, miR-449 microRNAs strongly accumulated in multiciliated cells. In both models, we show that miR-449 microRNAs promote centriole multiplication and multiciliogenesis by directly repressing the Delta/Notch pathway. We established Notch1 and its ligand Delta-like 1 (DLL1) as miR-449 bona de targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells thanin surrounding cells, decreased after miR-449 overexpression and increased after miR-449 inhibition. In frog, miR-449 silencing led to increased Dll1 expression. Consistently, overexpression of Dll1 mRNA lacking miR-449 target sites repressed multiciliogenesis, whereas both Dll1 and Notch1 knockdown rescued multiciliogenesis in miR-449-decient cells. Antisense-mediated protection of miR-449-binding sites of endogenous human Notch1 or frog Dll1 strongly repressed multiciliogenesis. Our results unravel a conserved mechanism whereby Notch signalling must undergo miR-449-mediated inhibition to permit differentiation of ciliated cell progenitors.
Motile cilia are microtubule-based organelles that develop from the apical surface of specialized cells in varying numbers, ranging from one to several hundred per cell1,2. They have important mechanical and sensory roles1,2, highlighted by the fact that a wide variety of human pathologies, such as chronic airway diseases (including primary ciliary
1CNRS, Institut de Pharmacologie Molculaire et Cellulaire, F06560 Sophia Antipolis, France. 2University of Nice-Sophia-Antipolis, F06560 Sophia Antipolis, France.
3CNRS, Institut de Biologie du Dveloppement de Marseille-Luminy, F13288 Marseille, France. 4University of Mditerrane, F13288 Marseille, France. 5INSERM, U903, F51092 Reims, France. 6University of Reims Champagne-Ardenne, F51092 Reims, France. 7INSERM, U876, F33076 Bordeaux, France. 8University of Bordeaux 2, F33076 Bordeaux, France. 9CHU de Nice, Service dHmatologie-Biologie, Hpital Pasteur, F06000 Nice, France. 10CHU de Nice, Service de Pdiatrie, Hpital lArchet 2, F06200 Nice, France. 11These authors contributed equally to this work. 12Co-senior authors.
13Correspondence should be...