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Heart, brain, and body wall defects in mice lacking calreticulin
F Rauch1, J Prud'homme, A Arabian
1Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, H3G 1A6, Canada.
Abstract:
Calreticulin is a ubiquitously expressed protein, which has been implicated in a large number of cellular functions, including calcium storage and signaling, protein folding, and cell attachment. To examine the role of calreticulin during in vivo development, mice deficient in calreticulin were generated by targeted inactivation of the calreticulin gene. Calreticulin-deficient mutants die in utero, mostly in late gestation. Half of these embryos had decreased cardiac cell mass, associated with increased apoptosis of cardiac myocytes. In vitro differentiation cultures of calreticulin-deficient embryonic stem cells resulted in fewer embryoid bodies with contractile activity than cultures derived from calreticulin +/- stem cells (P < 0.001). Sixteen percent of the mutants exhibited exencephaly secondary to a defect in neural tube closure. Embryos surviving until Embryonic Day 16.5 had omphalocele. Lack of calreticulin did not influence survival of embryonic fibroblasts under various endoplasmic reticulum stress conditions. However, calreticulin did influence cell migration in a calcium- and substrate-dependent manner. We conclude that calreticulin is not essential during the early stages of embryonic development, but is important for the development of heart and brain and for ventral body wall closure. The observed abnormalities are compatible with a role of calreticulin in the modulation of cellular calcium signaling.
Insights
Calreticulin deficiency in mice causes embryonic death, impacting heart and brain development and body wall closure. This suggests calreticulin is crucial for fetal development and calcium signaling.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Biology
Background:
- Calreticulin is a ubiquitous protein involved in calcium storage, signaling, protein folding, and cell attachment.
- Its precise role in in vivo development remains incompletely understood.
Purpose of the Study:
- To investigate the essential functions of calreticulin during embryonic development in vivo.
- To elucidate the consequences of calreticulin deficiency on organogenesis and cellular processes.
Main Methods:
- Generation of calreticulin-deficient mice via targeted gene inactivation.
- In vitro differentiation of calreticulin-deficient embryonic stem cells.
- Assessment of embryonic viability, cardiac development, neural tube closure, and cell migration.
Main Results:
- Calreticulin-deficient mice exhibit embryonic lethality, primarily in late gestation.
- Mutant embryos show decreased cardiac cell mass, increased cardiac myocyte apoptosis, and impaired embryoid body contractility.
- Defects in neural tube closure (exencephaly) and ventral body wall closure (omphalocele) were observed.
- Calreticulin influenced cell migration in a calcium- and substrate-dependent manner, but not fibroblast survival under ER stress.
Conclusions:
- Calreticulin is essential for normal embryonic development, particularly for heart and brain formation and ventral body wall closure.
- The observed developmental defects are consistent with a role for calreticulin in modulating cellular calcium signaling pathways.
- Calreticulin is not indispensable for early embryonic development or cellular responses to endoplasmic reticulum stress.