title: MicroRNA-23 restricts cardiac valve formation by inhibiting Has2 and extracellular hyaluronic acid production.
abstract: BACKGROUND
  Since their discovery almost 20 years ago, microRNAs have been shown to perform essential roles during tissue development and disease. Although roles for microRNAs in the myocardium during embryo development and cardiac disease have been demonstrated, very little is know about their role in the endocardium or during cardiac valve formation.
  
  
  OBJECTIVE
  To study the role of microRNAs in cardiac valve formation.
  
  
  RESULTS
  We show that zebrafish dicer mutant embryos, lacking mature miRNAs, form excessive endocardial cushions. By screening miRNAs expressed in the heart, we found that miR-23 is both necessary and sufficient for restricting the number of endocardial cells that differentiate into endocardial cushion cells. In addition, in mouse endothelial cells, miR-23 inhibited a transforming growth factor-β-induced endothelial-to-mesenchymal transition. By in silico screening of expression data with predicted miR-23 target sites combined with in vivo testing, we identified hyaluronic acid synthase 2 (Has2), Icat, and Tmem2 as novel direct targets of miR-23. Finally, we demonstrate that the upregulation of Has2, an extracellular remodeling enzyme required for endocardial cushion and valve formation, is responsible for the excessive endocardial cushion cell differentiation in dicer mutants.
  
  
  CONCLUSIONS
  MiR-23 in the embryonic heart is required to restrict endocardial cushion formation by inhibiting Has2 expression and extracellular hyaluronic acid production.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, CT Utrecht, The Netherlands.
authors.forename: Anne Karine
authors.initials: AK
authors.lastname: Lagendijk
authors.forename: Marie Jose
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Silja Barbara
authors.initials: SB
authors.lastname: Burkhard
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002452:Cell Count; D002454:Cell Differentiation; D002478:Cells, Cultured; D054089:Endocardial Cushions / Q000166:cytology / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D029961:Zebrafish Proteins; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; C491095:has2 protein, zebrafish