title: Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.
abstract: Multiciliated cells lining the surface of some vertebrate epithelia are essential for various physiological processes, such as airway cleansing. 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.
authors: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, F06560 Sophia Antipolis, France.
authors: Brice
authors: B
authors: Marcet
authors: Benoît
authors: B
authors: Chevalier
authors: Guillaume
authors: G
authors: Luxardi
authors: Christelle
authors: C
authors: Coraux
authors: Laure-Emmanuelle
authors: LE
authors: Zaragosi
authors: Marie
authors: M
authors: Cibois
authors: Karine
authors: K
authors: Robbe-Sermesant
authors: Thomas
authors: T
authors: Jolly
authors: Bruno
authors: B
authors: Cardinaud
authors: Chimène
authors: C
authors: Moreilhon
authors: Lisa
authors: L
authors: Giovannini-Chami
authors: Béatrice
authors: B
authors: Nawrocki-Raby
authors: Philippe
authors: P
authors: Birembaut
authors: Rainer
authors: R
authors: Waldmann
authors: Laurent
authors: L
authors: Kodjabachian
authors: Pascal
authors: P
authors: Barbry
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