Histone deacetylase is required for the activation of Wnt/β-catenin signaling crucial for heart valve formation in zebrafish embryos.
During vertebrate heart valve formation, Wnt/β-catenin signaling induces BMP signals in atrioventricular canal (AVC) myocardial cells and underlying AVC endocardial cells then undergo endothelial-mesenchymal transdifferentiation (EMT) by receiving this BMP signals. Histone deacetylases (HDACs) have been implicated in numerous developmental processes by regulating gene expression. However, their specific roles in controlling heart valve development are largely unexplored. To investigate the role of HDACs in vertebrate heart valve formation, we treated zebrafish embryos with trichostatin A (TSA), an inhibitor of class I and II HDACs, from 36 to 48 h post-fertilization (hpf) during which heart looping and valve formation occur. Following TSA treatment, abnormal linear heart tube development was observed. In these embryos, expression of AVC myocardial bmp4 and AVC endocardial notch1b genes was markedly reduced with subsequent failure of EMT in the AVC endocardial cells. However, LiCl-mediated activation of Wnt/β-catenin signaling was able to rescue defective heart tube formation, bmp4 and notch1b expression, and EMT in the AVC region. Taken together, our results demonstrated that HDAC activity plays a pivotal role in vertebrate heart tube formation by activating Wnt/β-catenin signaling which induces bmp4 expression in AVC myocardial cells.
School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea.
Young-Seop
YS
Kim
Myoung-Jin
MJ
Kim
Tae-Hee
TH
Koo
Jun-Dae
JD
Kim
Soonil
S
Koun
Hyung Jin
HJ
Ham
You Mie
YM
Lee
Myungchull
M
Rhee
Sang-Yeob
SY
Yeo
Tae-Lin
TL
Huh
D000107:Acetylation; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D054089:Endocardial Cushions / Q000196:embryology; D004699:Endocardium / Q000196:embryology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D038081:Organogenesis / Q000187:drug effects / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C561596:Notch1b protein, zebrafish; D051881:Receptor, Notch1; D029961:Zebrafish Proteins; D051176:beta Catenin; C525813:bmp4 protein, zebrafish; C012589:trichostatin A; D006655:Histone Deacetylases; D018021:Lithium Chloride