Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo |
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Authors: | Nishii Kiyomasa Morimoto Sachio Minakami Reiko Miyano Yumi Hashizume Kanako Ohta Mika Zhan Dong-Yun Lu Qun-Wei Shibata Yosaburo |
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Affiliation: | a Department of Developmental Molecular Anatomy, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan b Department of Clinical Pharmacology, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan c Department of Health Sciences, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan |
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Abstract: | 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 α-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. |
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Keywords: | cTnT Development Heart Myofibrillogenesis |
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