Calreticulin is essential for cardiac development.
Calreticulin is essential for cardiac development.
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DOI：
10.1083/jcb.144.5.857
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发表时间：
1999-03-08
影响因子：
7.8
通讯作者：
Michalak, M
中科院分区：
文献类型：
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作者：
Mesaeli, N;Nakamura, K;Zvaritch, E;Dickie, P;Dziak, E;Krause, K H;Opas, M;MacLennan, D H;Michalak, M
钙网蛋白（Calreticulin）是一种广泛存在于内质网中的钙结合蛋白，具有调节细胞内钙稳态、分子伴侣活性、激素介导的基因调控和细胞粘附等多种功能。为了了解钙网蛋白的生理功能，我们使用基因靶向来创建钙网蛋白的敲除小鼠。钙网蛋白基因破坏的纯合子小鼠出现脐膨出（脐疝吸收失败），并显示心室壁厚度和心室壁深层小梁间凹陷显著减少。使用在钙网蛋白启动子控制下表达绿色荧光蛋白报告基因的转基因小鼠来显示钙网蛋白基因在心脏发育的早期阶段在心血管系统中高度活化。钙网蛋白在发育中的心脏中也高度表达，但它只是成熟心脏的一个次要成分。缓激肽通过InsP 3依赖性途径诱导的Ca 2+释放在crt −/−细胞中受到抑制，表明钙网蛋白在Ca 2+稳态中起作用。钙网蛋白缺乏的细胞也表现出受损的活化T细胞核因子（NF-AT 3）转录因子的核输入，表明钙网蛋白作为Ca 2 +/钙调神经磷酸酶/NF-AT/加塔-4转录途径的组分在心脏发育中起作用。
Calreticulin is a ubiquitous Ca2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca2+ homeostasis, chaperone activity, steroid-mediated gene regulation, and cell adhesion. To understand the physiological function of calreticulin we used gene targeting to create a knockout mouse for calreticulin. Mice homozygous for the calreticulin gene disruption developed omphalocele (failure of absorption of the umbilical hernia) and showed a marked decrease in ventricular wall thickness and deep intertrabecular recesses in the ventricular walls. Transgenic mice expressing a green fluorescent protein reporter gene under the control of the calreticulin promoter were used to show that the calreticulin gene is highly activated in 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 Ca2+ release by the InsP3-dependent pathway was inhibited in crt −/− cells, suggesting 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 calreticulin plays a role in cardiac development as a component of the Ca2+/calcineurin/NF-AT/GATA-4 transcription pathway.