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© The Rockefeller University Press, 0021-9525/1999//857 $5.00
The Journal of Cell Biology, Volume 144, Number 5, , 1999 857-868

Regular Articles

Calreticulin Is Essential for Cardiac Development



Nasrin Mesaeli*, Kimitoshi Nakamura*, Elena Zvaritch{ddagger}, Peter Dickie§, Ewa Dziak||, Karl-Heinz Krause, Michal Opas||, David H. MacLennan{ddagger}, and Marek Michalak*

* Medical Research Council Group in Molecular Biology of Membranes, *Department of Biochemistry and § Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada TGG 2H7; {ddagger} Banting and Best Department of Medical Research, || Department of Anatomy and Cell Biology, University of Toronto, Toronto, Canada M5S 1A8; and Department of Geriatrics, Geneva University Hospitals, Geneva, Switzerland 1211 Geneve

Calreticulin is a ubiquitous Ca2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca2+ homeostasis, chaperone activity, steroid-mediated gene regulation, and cell adhesion. To understand the physiological function of calreticulin we used gene targeting to create a knockout mouse for calreticulin. Mice homozygous for the calreticulin gene disruption developed omphalocele (failure of absorption of the umbilical hernia) and showed a marked decrease in ventricular wall thickness and deep intertrabecular recesses in the ventricular walls. Transgenic mice expressing a green fluorescent protein reporter gene under the control of the calreticulin promoter were used to show that the calreticulin gene is highly activated in the cardiovascular system during the early stages of cardiac development. Calreticulin protein is also highly expressed in the developing heart, but it is only a minor component of the mature heart. Bradykinin-induced Ca2+ release by the InsP3-dependent pathway was inhibited in crt–/– cells, suggesting that calreticulin plays a role in Ca2+ homeostasis. Calreticulin-deficient cells also exhibited impaired nuclear import of nuclear factor of activated T cell (NF-AT3) transcription factor indicating that calreticulin plays a role in cardiac development as a component of the Ca2+/calcineurin/NF-AT/GATA-4 transcription pathway.

Key Words: cardiac development • NF-AT • calcineurin • endoplasmic reticulum • calcium binding protein • transcription

Abbreviations used in this paper: ES cells, embryonic stem cells; GFP, green fluorescent protein; InsP3, inositol 1,4,5-trisphosphate; NF-AT, nuclear factor of activated T cell.

Address correspondence to Dr. Marek Michalak, MRC Group in Molecular Biology of Membranes, Department of Biochemistry, 3-56 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Tel.: 780-492-2256. Fax: 780-492-0886. E-mail: marek.michalak @ualberta.ca


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