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In a gene trap experiment, we found that <jats:italic>vascular cell adhesion protein 1 isoform X2<\/jats:italic> (<jats:italic>VCAP1X2)<\/jats:italic> mutant embryos displayed a dilated cardiomyopathy phenotype, including reduced cardiac contractility, enlarged ventricular chamber and thinned ventricular compact layer. Cardiomyocyte and epicardial cell proliferation was decreased in the mutant heart ventricle, as was the expression of pAKT and pERK. Contractile dysfunction in the mutant was caused by sarcomeric disorganization, including sparse myofilament, blurred Z-disc, and decreased gene expression for sarcomere modulators (<jats:italic>smyd1b<\/jats:italic>, <jats:italic>mypn<\/jats:italic> and <jats:italic>fhl2a<\/jats:italic>), sarcomeric proteins (<jats:italic>myh6<\/jats:italic>, <jats:italic>myh7<\/jats:italic>, <jats:italic>vmhcl<\/jats:italic> and <jats:italic>tnnt2a<\/jats:italic>) and calcium regulators (<jats:italic>ryr2b<\/jats:italic> and <jats:italic>slc8a1a<\/jats:italic>). Treatment of PI3K activator restored Z-disc alignment while injection of <jats:italic>smyd1b<\/jats:italic> mRNA restored Z-disc alignment, contractile function and cardiomyocyte proliferation in ventricles of <jats:italic>VCAP1X2<\/jats:italic> mutant embryos. Furthermore, injection of <jats:italic>VCAP1X2<\/jats:italic> variant mRNA rescued all phenotypes, so long as two cytosolic tyrosines were left intact. Our results reveal two tyrosine residues located in the VCAP1X2 cytoplasmic domain are essential to regulate cardiac contractility and the proliferation of ventricular cardiomyocytes and epicardial cells through modulating pAKT and pERK expression levels.<\/jats:p>","DOI":"10.1038\/s41598-018-26110-3","type":"journal-article","created":{"date-parts":[[2018,5,14]],"date-time":"2018-05-14T14:12:13Z","timestamp":1526307133000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Zebrafish VCAP1X2 regulates cardiac contractility and proliferation of cardiomyocytes and epicardial cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Fang-Chi","family":"Hsieh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Fen","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Liau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Chang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Min","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Der","family":"Hsiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2554-3821","authenticated-orcid":false,"given":"Sheng-Ping L.","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,5,18]]},"reference":[{"key":"26110_CR1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/nrd4554","volume":"14","author":"PM Hwang","year":"2015","unstructured":"Hwang, P. 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