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Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse
Lei Guo1, Kimitoshi Nakamura, Jeffery Lynch
1Canadian 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.
Abstract:
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.
Insights
Calreticulin deficiency causes embryonic lethality due to heart defects. Overexpressing calcineurin rescues these mice, revealing calreticulin and calcineurin
Area of Science:
- Molecular Biology
- Cardiovascular Development
- Calcium Signaling
Background:
- Calreticulin is a crucial endoplasmic reticulum chaperone involved in calcium (Ca2+) binding.
- Calreticulin deficiency in mice leads to embryonic lethality, linked to impaired cardiac development.
- The precise molecular mechanisms behind this cardiac defect remain unclear.
Purpose of the Study:
- To investigate the molecular basis of cardiac developmental defects in calreticulin-deficient mice.
- To determine if modulating calcineurin activity can rescue the calreticulin-deficient phenotype.
Main Methods:
- Genetic manipulation to create calreticulin-deficient mice.
- Overexpression of activated calcineurin in calreticulin-deficient mouse models.
- Phenotypic analysis of cardiac development, survival rates, and metabolic parameters in rescued mice.
Main Results:
- Overexpression of activated calcineurin rescued calreticulin-deficient mice from embryonic lethality.
- Rescued mice exhibited normal cardiac development but displayed growth retardation, hypoglycemia, and altered lipid profiles (increased triacylglycerols and cholesterol).
- This highlights the critical role of the calreticulin-calcineurin interaction in Ca2+-dependent signaling during cardiac development.
Conclusions:
- Calreticulin and calcineurin are fundamental to Ca2+-dependent signaling pathways essential for normal cardiac development.
- The study elucidates the molecular basis for rescuing the calreticulin-deficient phenotype by modulating calcineurin activity.
- These findings provide insights into the intricate regulation of cardiac development by calcium-binding chaperones and signaling molecules.