Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse.
Calreticulin is an endoplasmic reticulum resident Ca(2+)-binding chaperone. The importance of the protein is illustrated by embryonic lethality because of impaired cardiac development in calreticulin-deficient mice. The molecular details underlying this phenotype are not understood. In this study, we show that overexpression of activated calcineurin reverses the defect in cardiac development observed in calreticulin-deficient mice and rescues them from embryonic lethality. The surviving mice show no defect in cardiac development but exhibited growth retardation, hypoglycemia, increased levels of serum triacylglycerols, and cholesterol. Reversal of embryonic lethality because of calreticulin deficiency by activated calcineurin underscores the impact of the calreticulin-calcineurin functions on the Ca(2+)-dependent signaling cascade during early cardiac development. These findings show that calreticulin and calcineurin play fundamental roles in Ca(2+)-dependent pathways essential for normal cardiac development and explain the molecular basis for the rescue of calreticulin-deficient phenotype.
Guo
Lei
L
Canadian Institutes of Health Research Membrane Protein Research Group, Canadian Institutes of Health Research Molecular and Cell Biology of Lipids Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Nakamura
Kimitoshi
K
Lynch
Jeffery
J
Opas
Michal
M
Olson
Eric N
EN
Agellon
Luis B
LB
Michalak
Marek
M
D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics*; D037282:Calreticulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005313:Fetal Death / Q000517:prevention & control*; D006321:Heart / Q000254:growth & development / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011247:Pregnancy; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D037282:Calreticulin; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D019703:Calcineurin