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Published 8 July 2002. doi:10.1083/jcb.200204092
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© The Rockefeller University Press, 0021-9525/2002/7/103 $5.00
The Journal of Cell Biology, Volume 158, Number 1, July 8, 2002 103-113

Article

 Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis

Jian Li1, Michel Pucéat2, Carmen Perez-Terzic2,4, Annabelle Mery2, Kimitoshi Nakamura3, Marek Michalak3, Karl-Heinz Krause1 and Marisa E. Jaconi1

1 Biology of Aging Laboratory, Department of Geriatrics, Geneva University Hospitals, Geneva 1225, Switzerland
2 CNRS UPR1086, Centre de Recherches de Biochime Macromoléculaire, Montpellier 34293, France
3 CIHR Membrane Protein Research Group and Department of Biochemistry, University of Alberta, Edmonton T6G2H7, Canada
4 Division of Cardiovascular Diseases, Deptartment of Medicine and Deptartment of Physical Medicine and Rehabilitation, Mayo Clinic, Mayo Foundation, Rochester, MN 55905

Address correspondence to Marisa E. Jaconi, Laboratory of Biology of Ageing, Department of Geriatrics, Geneva University Hospitals, 2 Chemin du Petit Bel-Air, 1225 Chene-Bourg, Geneva 1225, Switzerland. Tel.: 41-22-305-5460. Fax: 41-22-305-5455. E-mail: marisa.jaconi{at}medecine.unige.ch

Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca2+-binding protein that regulates diverse vital cell functions, including Ca2+ storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt-/- embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt-/- EBs, despite normal expression levels of cardiac transcription factors. Crt-/- EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt-/- phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca2+ with EGTA or BAPTA, or by inhibiting Ca2+/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca2+ concentration ([Ca2+]c) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt-/- cardiac cells in the absence of ionomycin-triggered [Ca2+]c increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca2+-dependent checkpoint critical for early events during cardiac myofibrillogenesis.

Key Words: calreticulin; Ca2+; embryonic stem cells; MEF2C; cardiac myofibrillogenesis


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