Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.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.
Ambros,
The functions of animal microRNAs.
2004, Pubmed
Ambros,
The functions of animal microRNAs.
2004,
Pubmed Cardinaud,
miR-34b/miR-34c: a regulator of TCL1 expression in 11q- chronic lymphocytic leukaemia?
2009,
Pubmed Choi,
Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430.
2007,
Pubmed Coraux,
Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration.
2008,
Pubmed Dawe,
Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells.
2007,
Pubmed Deblandre,
A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos.
1999,
Pubmed
,
Xenbase Essner,
Conserved function for embryonic nodal cilia.
2002,
Pubmed
,
Xenbase Eulalio,
Getting to the root of miRNA-mediated gene silencing.
2008,
Pubmed Feng,
miR-449 regulates CDK-Rb-E2F1 through an auto-regulatory feedback circuit.
2010,
Pubmed Flicek,
Ensembl 2008.
2008,
Pubmed Fliegauf,
When cilia go bad: cilia defects and ciliopathies.
2007,
Pubmed Guseh,
Notch signaling promotes airway mucous metaplasia and inhibits alveolar development.
2009,
Pubmed Hajj,
Basal cells of the human adult airway surface epithelium retain transit-amplifying cell properties.
2007,
Pubmed Hayes,
Identification of novel ciliogenesis factors using a new in vivo model for mucociliary epithelial development.
2007,
Pubmed
,
Xenbase Irizarry,
Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
2003,
Pubmed Kloosterman,
In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes.
2006,
Pubmed Le Brigand,
MiRonTop: mining microRNAs targets across large scale gene expression studies.
2010,
Pubmed Le Brigand,
Mediante: a web-based microarray data manager.
2007,
Pubmed LeSimple,
Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation.
2007,
Pubmed Lewis,
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
2005,
Pubmed Lizé,
E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis.
2010,
Pubmed Lizé,
MicroRNA-449a levels increase by several orders of magnitude during mucociliary differentiation of airway epithelia.
2010,
Pubmed López,
Notch activates sonic hedgehog and both are involved in the specification of dorsal midline cell-fates in Xenopus.
2003,
Pubmed
,
Xenbase Marcet,
Extracellular nucleotides regulate CCL20 release from human primary airway epithelial cells, monocytes and monocyte-derived dendritic cells.
2007,
Pubmed Marchal,
BMP inhibition initiates neural induction via FGF signaling and Zic genes.
2009,
Pubmed
,
Xenbase Marnellos,
Delta-Notch lateral inhibitory patterning in the emergence of ciliated cells in Xenopus: experimental observations and a gene network model.
2000,
Pubmed
,
Xenbase Mitchell,
A positive feedback mechanism governs the polarity and motion of motile cilia.
2007,
Pubmed
,
Xenbase Morichika,
Perturbation of Notch/Suppressor of Hairless pathway disturbs migration of primordial germ cells in Xenopus embryo.
2010,
Pubmed
,
Xenbase Ortholan,
MicroRNAs and lung cancer: new oncogenes and tumor suppressors, new prognostic factors and potential therapeutic targets.
2009,
Pubmed Pearson,
Centrioles want to move out and make cilia.
2007,
Pubmed Pohl,
Isolation and developmental expression of Xenopus FoxJ1 and FoxK1.
2004,
Pubmed
,
Xenbase Pottier,
Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions.
2009,
Pubmed Satir,
How did the cilium evolve?
2008,
Pubmed Shah,
Motile cilia of human airway epithelia are chemosensory.
2009,
Pubmed Stubbs,
The forkhead protein Foxj1 specifies node-like cilia in Xenopus and zebrafish embryos.
2008,
Pubmed
,
Xenbase Tamura,
MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0.
2007,
Pubmed Tsao,
Notch signaling controls the balance of ciliated and secretory cell fates in developing airways.
2009,
Pubmed Vladar,
Molecular characterization of centriole assembly in ciliated epithelial cells.
2007,
Pubmed Wanner,
Mucociliary clearance in the airways.
1996,
Pubmed Yang,
miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A.
2009,
Pubmed Zhen,
IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production.
2007,
Pubmed
