{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:35:42Z","timestamp":1762004142438,"version":"3.37.3"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2009,4,2]],"date-time":"2009-04-02T00:00:00Z","timestamp":1238630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"crossref","award":["MPO-36384"],"award-info":[{"award-number":["MPO-36384"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Heart and Stroke Foundation of Ontario","award":["T 6181"],"award-info":[{"award-number":["T 6181"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A role for calreticulin, an endoplasmic reticulum (ER)-resident, Ca2+-binding chaperone, has recently emerged in the context of cardiomyogenesis. We previously proposed calreticulin to be a novel cardiac fetal gene, because calreticulin knockout causes embryonic lethality in mice as a result of cardiac defects, it is transiently activated during heart development, and heart-targeted overexpression of constitutively active calcineurin in calreticulin-null mice rescues the lethal phenotype. Calreticulin affects Ca2+ homeostasis and expression of adhesion-related genes. Using cardiomyocytes derived from both calreticulin-null and wild-type embryonic stem (ES) cells, we show here that cardiomyogenesis from calreticulin-null ES cells is accelerated but deregulated, such that the myofibrils of calreticulin-null cardiomyocytes become disorganized and disintegrate with time in culture. We have previously shown that the disorganization of the actin cytoskeleton in calreticulin-null cells may be explained, at least in part, by the downregulation of adhesion proteins, implying that calreticulin ablation causes adhesion-related defects. Here, upon examination of adhesion proteins, we found that vinculin is downregulated in calreticulin-null cardiomyocytes. We also found c-Src activity to be higher in calreticulin-null cardiomyocytes than in wild-type cardiomyocytes, and c-Src activity is affected by both calreticulin and [Ca2+]. Finally, we show that calreticulin and calsequestrin, the major Ca2+ storage proteins of the ER and sarcoplasmic reticulum, respectively, exhibit alternate distributions. This suggests that calreticulin may have a housekeeping role to play in mature cardiomyocytes as well as during cardiomyogenesis. We propose here that calreticulin, an ER Ca2+ storage protein, is a crucial regulator of cardiomyogenesis whose presence is required for controlled cardiomyocyte development from ES cells.<\/jats:p>\n               <jats:p>Disclosure of potential conflicts of interest is found at the end of this article.<\/jats:p>","DOI":"10.1002\/stem.85","type":"journal-article","created":{"date-parts":[[2009,4,3]],"date-time":"2009-04-03T02:21:01Z","timestamp":1238725261000},"page":"1507-1515","source":"Crossref","is-referenced-by-count":16,"title":["Embryonic Stem Cell-Derived Cardiomyogenesis: A Novel Role for Calreticulin as a Regulator"],"prefix":"10.1093","volume":"27","author":[{"given":"Sylvia","family":"Papp","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Dziak","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Opas","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,4,2]]},"reference":[{"issue":"5","key":"2022011221401878300_bib1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1083\/jcb.144.5.857","article-title":"Calreticulin is essential for cardiac development","volume":"144","author":"Mesaeli","year":"1999","journal-title":"J Cell Biol"},{"key":"2022011221401878300_bib2","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1471-213X-6-54","article-title":"Ultrastructural analysis of development of myocardium in calreticulin-deficient mice","volume":"6","author":"Lozyk","year":"2006","journal-title":"BMC Dev Biol"},{"key":"2022011221401878300_bib3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0074-7696(05)45004-4","article-title":"Cellular functions of endoplasmic reticulum chaperones calreticulin, calnexin, and ERp57","volume":"245","author":"Bedard","year":"2005","journal-title":"Int Rev Cytol"},{"key":"2022011221401878300_bib4","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1091\/mbc.11.5.1845","article-title":"Inositol 1,4,5-trisphosphate directs Ca2+ flow between mitochondria and the endoplasmic\/sarcoplasmic reticulum: A role in regulating cardiac autonomic Ca2+ spiking","volume":"11","author":"Jaconi","year":"2000","journal-title":"Mol Biol Cell"},{"key":"2022011221401878300_bib5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1012209923231","article-title":"Endoplasmic reticulum in the heart, a forgotten organelle?","volume":"225","author":"Mesaeli","year":"2001","journal-title":"Mol Cell Biochem"},{"key":"2022011221401878300_bib6","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1056\/NEJM199910213411706","article-title":"Signaling pathways for cardiac hypertrophy and failure","volume":"341","author":"Hunter","year":"1999","journal-title":"N Engl J Med"},{"key":"2022011221401878300_bib7","doi-asserted-by":"crossref","first-page":"50776","DOI":"10.1074\/jbc.M209900200","article-title":"Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse","volume":"277","author":"Guo","year":"2002","journal-title":"J Biol Chem"},{"key":"2022011221401878300_bib8","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1172\/JCI12412","article-title":"Complete heart block and sudden death in mice overexpressing calreticulin","volume":"107","author":"Nakamura","year":"2001","journal-title":"J Clin Invest"},{"key":"2022011221401878300_bib9","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1006\/dbio.2002.0666","article-title":"Control of cardiac development by an evolutionarily conserved transcriptional network","volume":"246","author":"Cripps","year":"2002","journal-title":"Dev Biol"},{"key":"2022011221401878300_bib10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1083\/jcb.200412156","article-title":"Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca2+-dependent signaling cascade","volume":"170","author":"Lynch","year":"2005","journal-title":"J Cell Biol"},{"key":"2022011221401878300_bib11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.tcm.2006.01.004","article-title":"Assembling pieces of the cardiac puzzle; 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