Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo
Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo
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DOI：
10.1016/j.ydbio.2008.07.007
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发表时间：
2008-10-01
影响因子：
2.7
通讯作者：
Shibata, Yosaburo
中科院分区：
文献类型：
--
作者：
Nishii, Kiyomasa;Morimoto, Sachio;Shibata, Yosaburo
心肌肌钙蛋白T(CTnT)是心肌细胞中肌钙蛋白(Tn)复合体的一个组成部分，通过将另外两个TN组分--肌钙蛋白I(TnI)和肌钙蛋白C(TnC)锚定在原肌球蛋白(TM)上，对心肌收缩起着调节作用。为了确定cTnT在体内的功能，我们在小鼠的TNNT2基因座上创建了一个空的cTnT等位基因。在cTnT缺陷(cTnT(-/-))的心肌细胞中，粗丝和细丝以及α-肌动蛋白阳性的Z盘样结构没有组装成肌节，由于缺乏心跳而导致早期胚胎死亡。在不含cTnT的细丝中，TnI与TM解离。尽管cTnT-/-心肌细胞细丝上的TN丢失，但表现出有规律的钙瞬变。这些发现表明，cTnT在胚胎心脏肌原纤维形成过程中的肌节组装中起着关键作用，同时也表明膜兴奋和细胞内钙处理系统的发展独立于收缩系统。相比之下，cTnT(+/-)杂合小鼠的寿命正常，心脏没有结构和功能异常，这表明单倍体功能不全可能不是心肌病的潜在原因，已知的心肌病与TNNT2基因的各种突变有关。(C)2008 Elsevier Inc.保留所有权利。
Cardiac troponin T (cTnT) is a component of the troponin (Tn) complex in cardiac myocytes, and plays a regulatory role in cardiac muscle contraction by anchoring two other Tn components, troponin I (TnI) and troponin C, to tropomyosin (Tm) on the thin filaments. In order to determine the in vivo function of cTnT, we created a null cTnT allele in the mouse TNNT2 locus. In cTnT-deficient (cTnT(-/-)) cardiac myocytes, the thick and thin filaments and alpha-actinin-positive Z-disk-like Structures were not assembled into sarcomere, causing early embryonic lethality due to a lack of heartbeats. TnI was dissociated from Tm in the thin filaments without cTnT. In spite of loss of Tn on the thin filaments, the cTnT-/- cardiac myocytes showed regular Ca2+- transients. These findings indicate that cTnT plays a critical role in sarcomere assembly during myofibrillogenesis in the embryonic heart, and also indicate that the membrane excitation and intracellular Ca2+ handling systems develop independently of the contractile system. In contrast, heterozygous cTnT(+/-) mice had a normal life span with no structural and functional abnormalities in their hearts, suggesting that haploinsufficiency could not be a potential cause of cardiomyopathies, known to be associated with a variety of mutations in the TNNT2 locus. (c) 2008 Elsevier Inc. All rights reserved.