T-box factors determine cardiac design.

Heart Failure Research Center, Department of Anatomy and Embryology, Academic Medical Center, Amsterdam, The Netherlands.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 04/2007; 64(6):646-60.
Source: PubMed


The heart of higher vertebrates is a structurally complicated multi-chambered pump that contracts synchronously. For its proper function a number of distinct integrated components have to be generated, including force-generating compartments, unidirectional valves, septa and a system in charge of the initiation and coordinated propagation of the depolarizing impulse over the heart. Not surprisingly, a large number of regulating factors are involved in these processes that act in complex and intertwined pathways to regulate the activity of target genes responsible for morphogenesis and function. The finding that mutations in T-box transcription factor-encoding genes in humans lead to congenital heart defects has focused attention on the importance of this family of regulators in heart development. Functional and genetic analyses in a variety of divergent species has demonstrated the critical roles of multiple T-box factor gene family members, including Tbx11, -2, -3, -5, -18 and -20, in the patterning, recruitment, specification, differentiation and growth processes underlying formation and integration of the heart components. Insight into the roles of T-box factors in these processes will enhance our understanding of heart formation and the underlying molecular regulatory pathways.

1 Follower
8 Reads
  • Source
    • "This suggests that chamber formation should be repressed regionally and, consequently, that maintenance of primary myocardium is crucial for the localized formation of the chamber. Two closely related transcription factors of the T-box gene family, Tbx2 and Tbx3, are involved in this repression [75] [76] [77] [78]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early cardiac development involves the formation of a heart tube, looping of the tube and formation of chambers. These processes are highly similar among all vertebrates, which suggest the existence of evolutionary conservation of the building plan of the heart. From the jawless lampreys to man, T-box transcription factors like Tbx5 and Tbx20 are fundamental for heart formation, whereas Tbx2 and Tbx3 repress chamber formation on the sinu-atrial and atrioventricular borders. Also, electrocardiograms from different vertebrates are alike, even though the fish heart only has two chambers whereas the mammalian heart has four chambers divided by septa and in addition has much higher heart rates. We conclude that most features of the high-performance hearts of mammals and birds can be traced back to less developed traits in the hearts of ectothermic vertebrates. This article is part of a Special Issue entitled: Cardiomyocyte biology: Cardiac pathways of differentiation, metabolism and contraction.
    Biochimica et Biophysica Acta 10/2012; 1833(4). DOI:10.1016/j.bbamcr.2012.10.004 · 4.66 Impact Factor
  • Source
    • "Both of these elements will define the ultimate transcriptional function of the factor and hence its downstream gene targets. The T-box factors Tbx2, Tbx3 and Tbx5 are known, for instance, to bind the homeobox protein Nkx2.5 [13, 17–19]. Since T-box factors are expressed and are required for the development of many different organs and tissues, complex forming with a factor such as Nkx2.5, which has a more cardiac-restricted expression pattern, may be instrumental in determining a set of heart specific T-box target genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize extensively in the embryo including the atrioventricular and outflow tract cushion mesenchyme and a small area of interventricular myocardium. Tbx3, SOX4, and SOX2 ChIP data, identify a region in intron 1 of Gja1 bound by all tree proteins and subsequent ChIP experiments verify that this sequence is bound, in vivo, in the developing heart. In a luciferase reporter assay, this element displays a synergistic antagonistic response to co-transfection of Tbx3 and Sox4 and in vivo, in zebrafish, drives expression of a reporter in the heart, confirming its function as a cardiac enhancer. Mechanistically, we postulate that Sox4 is a mediator of Tbx3 transcriptional activity. Electronic supplementary material The online version of this article (doi:10.1007/s00018-011-0693-7) contains supplementary material, which is available to authorized users.
    Cellular and Molecular Life Sciences CMLS 05/2011; 68(23):3949-61. DOI:10.1007/s00018-011-0693-7 · 5.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart cells are the unitary elements that define cardiac function and disease. The recent identification of distinct families of cardiovascular progenitor cells begins to build a foundation for our understanding of the developmental logic of human cardiovascular disease, and also points to new approaches to arrest and/or reverse its progression, a major goal of regenerative medicine. In this review, we highlight recent clarifications, revisions, and advances in our understanding of the many lives of a heart cell, with a primary focus on the emerging links between cardiogenesis and heart stem cell biology.
    Cell stem cell 05/2008; 2(4):320-31. DOI:10.1016/j.stem.2008.03.010 · 22.27 Impact Factor
Show more


8 Reads
Available from