T-box factors determine cardiac design

Abstract

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.

Figure 1

Schematic overview of the different cardiac progenitor populations. Precursors of the embryonic ventricle (ev), the future left ventricle (lv), are mainly derived from the first heart field (light gray), whereas precursors of the outflow tract (oft), right ventricle (rv) and atria (left atrium, la; right atrium, ra) are derived from the second heart field (gray). The Tbx18+ caudal heart field (dark gray) forms the sinus horns (sh). A, anterior; L, left; P, posterior; R, right.

Figure 2

Schematic overview of heart development in higher vertebrates. Chamber myocardium (red, ventricular; blue, atrial) expands from the outer curvatures of the primary heart tube, whereas non-chamber myocardium (gray) of the inflow tract (ift), sinus horns (sh), atrioventricular canal (avc), outflow tract (oft) and inner curvatures does not expand. Sinus horn myocardium gives rise to the sinoatrial node (san), atrioventricular canal myocardium to the atrioventricular node (avn) and atrioventricular junction. The first three panels show the left-lateral view. A, anterior; D, dorsal; P, posterior; V, ventral; a, atrium; avb, atrioventricular bundle; avc, atrioventricular canal; ev, embryonic ventricle; la, left atria; lv, left ventricle; ra, right atrium; rv, right ventricle.

Figure 3

Transverse serial sections of an E9.5 mouse embryo showing the expression of T-box genes in the heart. (a) T-box expression patterns in the inflow tract/dorsal mesocardium region compared with second heart field marker Isl1 and myocardial marker Mlc2a. The black arrows depict the dorsal posterior region of the Isl1 ⁺ second heart field, which expresses Tbx5 and Tbx20. The red arrows depict the caudal heart field, which only expresses Tbx18. (b) T-box expression patterns in the outflow tract/pharyngeal region. The black arrows and red arrows depict the pericardial mesothelium and mesenchyme, respectively, of the anterior region of the second heart field, which expresses Tbx20, Tbx2 and Tbx3. Note the expression of Tbx5 and Tbx18 in the proepicardium (pe). The asterisk marks the atrioventricular cushion mesenchyme expressing Tbx20, Tbx2 and Tbx3. avc, atrioventricular canal; ep, epicardium; la, left atrium; lccv, left common cardinal vein; pe, proepicardium; pa, pharyngeal arches; ra, right atrium; rv, right ventricle; st, septum transversum.

Figure 4

Role of T-box factors in early heart development. (a) Schematic representation of an E9.5-10.5 heart showing T-box patterning in the different emerging structures. Tbx2 and Tbx3 exert their function in the non-chamber myocardium, Tbx1 in the outflow tract and Tbx18 in the sinus horns. Yellow bars indicate expression patterns of Tbx5, Tbx20 and Nkx2-5. Tbx5 is required for antero-posterior patterning and, along with Tbx20 and Nkx2-5, for chamber differentiation. Note the absence of Nkx2-5 expression from the sinus horns. (b) Working model of a T-box factor regulatory network for chamber formation. Tbx2 and Tbx3 act as repressors of chamber differentiation in primary myocardium where they compete with Tbx5, while BMP signaling stimulates Tbx2/3 (and Tbx20) expression in the primary myocardium. Tbx20 represses Tbx2 expression in chamber myocardium and regulates proliferation. Tbx5 acts as a positive regulator of chamber genes and proliferation, thus stimulating chamber differentiation.