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 sig naling, protein folding, and cell attachment. To examine the role of calret iculin during in vivo development, mice deficient in calreticulin were gene rated by targeted inactivation of the calreticulin gene. Calreticulin-defic ient mutants die in utero, mostly in late gestation. Half of these embryos had decreased cardiac cell mass, associated with increased apoptosis of car diac myocytes, In vitro differentiation cultures of calreticulin-deficient embryonic stem cells resulted in fewer embryoid bodies with contractile act ivity than cultures derived from calreticulin +/- stem cells (P < 0.001). S ixteen percent of the mutants exhibited exencephaly secondary to a defect i n neural tube closure. Embryos surviving until Embryonic Day 16.5 had ompha locele. Lack of calreticulin did not influence survival of embryonic fibrob lasts under various endoplasmic reticulum stress conditions. However, calre ticulin did influence cell migration in a calcium- and substrate-dependent manner. We conclude that calreticulin is not essential during the early sta ges of embryonic development, but is important for the development of heart and brain and for ventral body wall closure. The observed abnormalities ar e compatible with a role of calreticulin in the modulation of cellular calc ium signaling. (C) 2000 Academic Press.