Calreticulin-Dependent Signaling During Embryonic Development

Abstract

Ca²⁺ ions are signaling molecules responsible for controlling developmental processes, including fertilization, differentiation, proliferation, and transcription factor activation. Various cellular functions are regulated by changes in cytoplasmic Ca²⁺, including gene transcription and expression, protein synthesis, modification, folding and secretion, cell motility, cytoplasmic and mitochondrial energy metabolism, cell cycle progression, and apoptosis. Endoplasmic reticulum is an important Ca²⁺ storage organelle involved in virtually every aspect of Ca²⁺ homeostasis. Endoplasmic reticulum luminal Ca²⁺-binding chaperones such as calreticulin are critical for buffering endoplasmic reticulum Ca²⁺. In mice, calreticulin deficiency is lethal in utero because of the compromised Ca²⁺ storage capacity in the endoplasmic reticulum and disrupted InsP₃ receptor-mediated Ca²⁺ release. A disturbance in Ca²⁺ release results in impaired cardiac development due to inhibited Ca²⁺-dependent transcriptional pathways. Calreticulin and the endoplasmic reticulum are the key upstream elements for calcineurin in Ca²⁺-signaling pathways. In contrast upregulation of calreticulin and overloading endoplasmic reticulum with Ca²⁺ leads to cardiac arrhythmias and impaired development of the cardiac conductive system.