Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo.
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 Ca(2+)-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 Ca(2+) 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.
Nishii
Kiyomasa
K
Department of Developmental Molecular Anatomy, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan. nishii@m.u-tokyo.ac.jp
Morimoto
Sachio
S
Minakami
Reiko
R
Miyano
Yumi
Y
Hashizume
Kanako
K
Ohta
Mika
M
Zhan
Dong-Yun
DY
Lu
Qun-Wei
QW
Shibata
Yosaburo
Y
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D020013:Calcium Signaling / Q000235:genetics; D004452:Echocardiography; D004622:Embryo, Mammalian; D018390:Gene Targeting; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006340:Heart Rate, Fetal / Q000235:genetics; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism*; D014335:Tropomyosin / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000502:physiology*
D000199:Actins; D014335:Tropomyosin; D020107:Troponin T; D000185:Actinin