Calreticulin Is Essential for Cardiac Development

Calreticulin Is Essential for Cardiac Development Calreticulin is a ubiquitous Ca 2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca 2+ 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 Ca 2+ release by the InsP 3 -dependent pathway was inhibited in crt −/− cells, suggesting that calreticulin plays a role in Ca 2+ 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 Ca 2+ /calcineurin/NF-AT/GATA-4 transcription pathway. cardiac development NF-AT calcineurin endoplasmic reticulum calcium binding protein transcription Footnotes 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 Abbreviations used in this paper: ES cells embryonic stem cells GFP green fluorescent protein InsP 3 inositol 1,4,5-trisphosphate NF-AT nuclear factor of activated T cell Submitted: 29 September 1998 Revision received 8 January 1999 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

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Publisher
Rockefeller University Press
Copyright
© 1999 Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
D.O.I.
10.1083/jcb.144.5.857
Publisher site
See Article on Publisher Site

Abstract

Calreticulin is a ubiquitous Ca 2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca 2+ 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 Ca 2+ release by the InsP 3 -dependent pathway was inhibited in crt −/− cells, suggesting that calreticulin plays a role in Ca 2+ 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 Ca 2+ /calcineurin/NF-AT/GATA-4 transcription pathway. cardiac development NF-AT calcineurin endoplasmic reticulum calcium binding protein transcription Footnotes 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 Abbreviations used in this paper: ES cells embryonic stem cells GFP green fluorescent protein InsP 3 inositol 1,4,5-trisphosphate NF-AT nuclear factor of activated T cell Submitted: 29 September 1998 Revision received 8 January 1999

Journal

The Journal of Cell BiologyRockefeller University Press

Published: Mar 8, 1999

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