Heart, brain, and body wall defects in mice lacking calreticulin.
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.
Rauch
F
F
Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, H3G 1A6, Canada.
Prud'homme
J
J
Arabian
A
A
Dedhar
S
S
St-Arnaud
R
R
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D037282:Calreticulin; D004622:Embryo, Mammalian / Q000473:pathology; D005313:Fetal Death; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D006554:Hernia, Umbilical / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D012261:Ribonucleoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D002135:Calcium-Binding Proteins; D037282:Calreticulin; D018832:Molecular Chaperones; D012261:Ribonucleoproteins