title: Protein kinase D2 controls cardiac valve formation in zebrafish by regulating histone deacetylase 5 activity.
abstract: BACKGROUND
  The molecular mechanisms that guide heart valve formation are not well understood. However, elucidation of the genetic basis of congenital heart disease is one of the prerequisites for the development of tissue-engineered heart valves.
  
  
  RESULTS
  We isolated here a mutation in zebrafish, bungee (bng(jh177)), which selectively perturbs valve formation in the embryonic heart by abrogating endocardial Notch signaling in cardiac cushions. We found by positional cloning that the bng phenotype is caused by a missense mutation (Y849N) in zebrafish protein kinase D2 (pkd2). The bng mutation selectively impairs PKD2 kinase activity and hence Histone deacetylase 5 phosphorylation, nuclear export, and inactivation. As a result, the expression of Histone deacetylase 5 target genes Krüppel-like factor 2a and 4a, transcription factors known to be pivotal for heart valve formation and to act upstream of Notch signaling, is severely downregulated in bungee (bng) mutant embryos. Accordingly, the expression of Notch target genes, such as Hey1, Hey2, and HeyL, is severely decreased in bng mutant embryos. Remarkably, downregulation of Histone deacetylase 5 activity in homozygous bng mutant embryos can rescue the mutant phenotype and reconstitutes notch1b expression in atrioventricular endocardial cells.
  
  
  CONCLUSIONS
  We demonstrate for the first time that proper heart valve formation critically depends on Protein kinase D2-Histone deacetylase 5-Krüppel-like factor signaling.
authors: Department of Medicine II, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors: Steffen
authors: S
authors: Just
authors: Ina M
authors: IM
authors: Berger
authors: Benjamin
authors: B
authors: Meder
authors: Johannes
authors: J
authors: Backs
authors: Andreas
authors: A
authors: Keller
authors: Sabine
authors: S
authors: Marquart
authors: Karen
authors: K
authors: Frese
authors: Eva
authors: E
authors: Patzel
authors: Gerd-Jörg
authors: GJ
authors: Rauch
authors: Hugo A
authors: HA
authors: Katus
authors: Wolfgang
authors: W
authors: Rottbauer
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D006351:Heart Valves / Q000196:embryology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D023421:Models, Animal; D020125:Mutation, Missense / Q000235:genetics; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D051881:Receptor, Notch1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology
chemical_list: C436494:Klf2a protein, zebrafish; D051741:Kruppel-Like Transcription Factors; C561596:Notch1b protein, zebrafish; D000091283:Protein Kinase D2; D051881:Receptor, Notch1; D029961:Zebrafish Proteins; C418487:klf4 protein, zebrafish; D011494:Protein Kinases; C561595:HDAC5 protein, zebrafish; D006655:Histone Deacetylases