TY - JOUR
T1 - Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo
AU - Nishii, Kiyomasa
AU - Morimoto, Sachio
AU - Minakami, Reiko
AU - Miyano, Yumi
AU - Hashizume, Kanako
AU - Ohta, Mika
AU - Zhan, Dong Yun
AU - Lu, Qun Wei
AU - Shibata, Yosaburo
N1 - Funding Information:
We thank Mamiko Kamizono and Takeyo Omura for their care of the experimental animals, Dr. Iwao Ohtsuki (of Jikei University Medical School) for the valuable discussions, and Dr. Benjamin Stephens for the critical reading of the manuscript. This work was supported by Grants-in-Aids for Scientific Research from the Japan Society for the Promotion of Science (No. 16790126 to K.N., No.15300136 and 17300129 to S.M, and No. 17390052 to Y.S.), and Special Coordination Funds from the Ministry of Education, Culture, Sports, Science and Technology (to S.M.). D.-Y.Z. is an Uehara Memorial Foundation Research Fellow, and Q.-W.L. is a recipient of JPSP Postdoctoral Fellowship for Foreign Researchers.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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.
AB - 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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U2 - 10.1016/j.ydbio.2008.07.007
DO - 10.1016/j.ydbio.2008.07.007
M3 - Article
C2 - 18671960
AN - SCOPUS:52049099588
VL - 322
SP - 65
EP - 73
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 1
ER -