Calreticulin is essential for cardiac development

Calreticulin is a ubiquitous Ca2+ binding protein, located in the endoplasm ic reticulum lumen, which has been implicated in many diverse functions inc luding: regulation of intracellular Ca2+ homeostasis, chaperone activity st eroid-mediated gene regulation, and cell adhesion. To understand the physio logical function of calreticulin we used gene targeting to create a knockou t mouse for calreticulin. Mice homozygous for the calreticulin gene disrupt ion developed omphalocele (failure of absorption of the umbilical hernia) a nd showed a marked decrease in ventricular wall thickness and deep intertra becular recesses in the ventricular walls. Transgenic mice expressing a gre en fluorescent protein reporter gene under the control of the calreticulin promoter were used to show that the calreticulin gene is highly activated i n the cardiovascular system during the early stages of cardiac development. Calreticulin protein is also highly expressed in the developing heart, but it is only a minor component of the mature heart. Bradykinin-induced Ca2release by the InsP(3)-dependent pathway was inhibited in crt(-/-) cells, s uggesting that calreticulin plays a role in Ca2+ homeostasis. Calreticulin- deficient cells also exhibited impaired nuclear import of nuclear factor of activated T cell (NF-AT3) transcription factor indicating that calreticuli n plays a role in cardiac development as a component of the Ca2+/calcineuri n/NF-AT/GATA-4 transcription pathway.