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First published online October 28, 2005
doi: 10.1242/10.1242/dev.02099

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T-box transcription factors and their roles in regulatory hierarchies in the developing heart

¹ Victor Chang Cardiac Research Institute, St Vincent's Hospital, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia
² Faculties of Medicine and Life Sciences, University of New South Wales, Kensington, New South Wales 2056, Australia

View larger version (64K): [in a new window]   Fig. 1. First and second heart lineages. (A) The second lineage of cardiac progenitor cells is highlighted in a cardiac crescent-stage mouse embryo (E7.5) by the expression of a ß-galactosidase (lacZ) transgene under the transcriptional control of the Fgf10 locus (arrows). (B) Expression of -cardiac actin mRNA in differentiating cardiomyocytes of the cardiac crescent (first lineage) in a similarly staged mouse embryo. Comparison with staining in A demonstrates that the second lineage progenitors lie medial and caudal to the first lineage progenitors of the crescent. (C) Transverse section through an E8.5 mouse embryo, showing expression of the Fgf10-lacZ transgene in dorsal pericardial mesoderm (DPM) in continuity with myocardium of the heart tube (HT), and in pharyngeal arch mesoderm (PAM). (D) Illustration of the position of the first (red) and second (green) heart precursor lineages at E7.5 (small inset), and during deployment to the heart tube at E8.5 (main figure) in the mouse embryo. Arrows indicate deployment at both poles of the heart. Large inset shows the contribution of the first and second heart lineages to the E11.5 heart. Figures reprinted, with permission, from Kelly and Harvey (Kelly and Harvey, 2004), and Parmacek and Epstein (Parmacek and Epstein, 2005), Copyright 2005 with permission from Elsevier. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

View larger version (63K): [in a new window]   Fig. 2. Chamber and non-chamber myocardium in the forming heart. (A-D) Illustrations of the developing mouse heart at E8.0 (A), E9.5 (B) and E11.5 (C), showing non-chamber (primary) myocardium (grey), ventricular chamber myocardium (red), atrial chamber myocardium (blue), and the inflow and outflow vessels (green). Note that chamber myocardium forms at the outer curvature of the looping heart tube. Components in the forming heart (A-C) can be traced to the adult heart (D). Primary myocardium forms the elements of the central conduction system (see Box 3), including the sinuatrial node (san), atrioventricular node (avn), atrioventricular bundle (avb; bundle of His) and bundle branches (bb), as well as insulating tissue of the atrioventricular junction (avj). Distal bundle branches (dbb) and Purkinje fibres (pf) form within the interventricular septum (IVS) and ventricular chambers, respectively. Yellow indicates the derivatives of the AV canal, including insulating elements formed from myocardium and valve leaflets formed from endocardial cushions. Modified from Christoffels et al. (Christoffels et al., 2004a), Copyright 2004 with permission from Elsevier. (E-J) In situ hybridization analysis of sections of E8.75-E9.5 mouse embryos showing mutually exclusive expression patterns of the heart chamber marker Nppa (E-G) and Tbx2, a marker of non-chamber myocardium (H-J, arrows). Reproduced with permission from Habets et al. (Habets et al., 2002). a, atrium; avc, atrioventricular canal; ev, embryonic ventricle; fg, foregut; icv, inferior caval vein; ift, inflow tract; la, left atrium; lv, left ventricle; oft, outflow tract; oftc, outflow tract cushion; pa, pharyngeal arch; ra, right atrium; rv, right ventricle; scv, superior caval vein.

View larger version (103K): [in a new window]   Fig. 3. T-box gene mutant phenotypes in mice. (A,B) Scanning electron micrographs showing hearts from wild-type (wt; A) and Tbx20–/– (B) E9.0 embryos (scale bars indicate relative size), showing hypoplasia, lack of looping and abnormal chamber development in the mutant. (C) In situ hybridization showing expression of cardiac marker Nkx2-5 in wild-type and Tbx5–/– E8.5 embryos, demonstrating a severe reduction of the LV and SA region in the mutant. (D-J) Comparison of Tbx20–/– embryos with wild-type siblings at E8.5, showing upregulation of Tbx2 (D), reduced proliferation (immunostaining for phosphohistone H3; arrows indicate the heart tube; E-F) and downregulation of cell-cycle gene Nmyc1 (G-J) in mutants. G,H are at the level of the OFT, I,J are at the level of the AVC. Figures reproduced from Bruneau et al., Cai et al. and Stennard et al. (Bruneau et al., 2001; Cai et al., 2005; Stennard et al., 2003), with permission from Elsevier and Company of Biologists Limited. avc, atrioventricular canal; iv, inflow ventricle-like chamber; lv, left ventricle; oft, outflow tract; ov, outflow ventricle-like chamber; rv, right ventricle; sa, sinuatrium.

View larger version (23K): [in a new window]   Fig. 4. Model of T-box transcription factor regulation of cardiac chamber development. Chamber myocardium is shown in red and non-chamber (primary) myocardium is shown in grey. Interactions between T-box genes in each of these compartments are indicated, with the relative expression levels of genes, as determined by positive and repressive interactions, reflected in the size of the lettering. Factor X (blue) is proposed to activate Tbx2 in non-chamber myocardium through repression of the Tbx2 inhibitory activity of Tbx20.

View larger version (79K): [in a new window]   Fig. 5. Cardiac defects resulting from partial RNAi knockdown of Tbx20. Rendered optical projection tomography (OPT) images of hearts from wild-type (WT; A-C) and RNAi knockdown (a4; D-F) E12.5 mouse embryos. Embryonic stem cells from which knockdown embryos were derived had a 65% reduction in Tbx20 mRNA levels and a 40% reduction in protein levels compared with wild type. (A,D) Surface rendered view. (B,C,E,F) Space-filling images of chamber lumina showing atria in purple (removed in C,F), ventricles in dark red, pulmonary artery in blue and aorta in red. Note the hypoplastic right ventricle and the lack of outflow vessel spiraling in the knockdown heart. Reproduced from Takeuchi et al. (Takeuchi et al., 2005), with permission from Company of Biologists Limited. la, left atrium; lv, left ventricle; ot, outflow tract; ra, right atrium; rv, right ventricle.