Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch path
Author: ["Brice Marcet","Benoît Chevalier","Guillaume Luxardi","Christelle Coraux","Laure-Emmanuelle Zaragosi","Marie Cibois","Karine Robbe-Sermesant","Thomas Jolly","Bruno Cardinaud","Chimène Moreilhon","Lisa Giovannini-Chami","Béatrice Nawrocki-Raby","Philippe Birembaut","Rainer Waldmann","Laurent Kodjabachian","Pascal Barbry"]
Publication: Nature Cell Biology
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Abstract
The mechanisms governing the biosynthesis of multiple motile cilia in vertebrates remain largely elusive. miR-449 accumulates specifically in multiciliated cells of Xenopus skin and human lung to promote multicilia formation through modulation of Notch signalling. Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing1,2,3. 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 fide targets. Human DLL1 and NOTCH1 protein levels were lower in multiciliated cells than in 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-deficient 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.
Cite this article
Marcet, B., Chevalier, B., Luxardi, G. et al. Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway. Nat Cell Biol 13, 693–699 (2011). https://doi.org/10.1038/ncb2241
