Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis.
TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.
Department of Pediatrics, University of Utah, Salt Lake City, UT 84158, USA.
Deborah U
DU
Frank
Kandis L
KL
Carter
Kirk R
KR
Thomas
R Michael
RM
Burr
Martijn L
ML
Bakker
William A
WA
Coetzee
Martin
M
Tristani-Firouzi
Michael J
MJ
Bamshad
Vincent M
VM
Christoffels
Anne M
AM
Moon
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D054537:Atrioventricular Block / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D001283:Atrioventricular Node / Q000473:pathology / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism; D004562:Electrocardiography; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006329:Heart Conduction System / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D016019:Survival Analysis; D020825:T-Box Domain Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography
D018031:Connexin 43; D007473:Ion Channels; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse