title: The mediator complex subunit Med10 regulates heart valve formation in zebrafish by controlling Tbx2b-mediated Has2 expression and cardiac jelly formation.
abstract: In search for novel key regulators of cardiac valve formation, we isolated the zebrafish cardiac valve mutant ping pong (png). We find that an insertional promoter mutation within the zebrafish mediator complex subunit 10 (med10) gene is leading to impaired heart valve formation. Expression of the T-box transcription factor 2b (Tbx2b), known to be essential in cardiac valve development, is severely reduced in png mutant hearts. We demonstrate here that transient reconstitution of Tbx2b expression rescues AV canal development in png mutant zebrafish. By contrast, overexpression of Forkhead box N4 (Foxn4), a known upstream regulator of Tbx2b, is not capable to reconstitute tbx2b expression and heart valve formation in Med10-deficient png mutant hearts. Interestingly, hyaluronan synthase 2 (has2), a known downstream target of Tbx2 and producer of hyaluronan (HA) - a major ECM component of the cardiac jelly and critical for proper heart valve development - is completely absent in ping pong mutant hearts. We propose here a rather unique role of Med10 in orchestrating cardiac valve formation by mediating Foxn4 dependent tbx2b transcription, expression of Has2 and subsequently proper development of the cardiac jelly.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany. Electronic address: steffen.just@uniklinik-ulm.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hirth
authors.affiliation: Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Berger
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Fishman
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany. Electronic address: wolfgang.rottbauer@uniklinik-ulm.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism; D000076002:Hyaluronan Synthases; D056892:Mediator Complex / Q000502:physiology*; D009154:Mutation; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; D056892:Mediator Complex; D020825:T-Box Domain Proteins; D029961:Zebrafish Proteins; C120107:tbx2b protein, zebrafish; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; C491095:has2 protein, zebrafish
keywords: Foxn4; Has2; Med10; Tbx2b; Valve formation; Zebrafish