T‐Box Genes: Developmental Functions in Mammals


Transcription factors encoded by the T‐box gene family control key functions throughout development in all metazoans. The DNA (deoxyribonucleic acid)‐binding domain is highly conserved. There are 17 genes in mouse and human, all with diverse functional roles from early embryogenesis through organogenesis and tissue homeostasis. The same gene may function in different tissues and at different stages such that mutation phenotypes can be complex. Most T‐box mutations display heterozygous defects, indicating dose sensitivity. Several T‐box genes affect pluripotency and differentiation in the pre‐ and early postimplantation embryo; limb outgrowth and differentiation is a major developmental area affected by T‐box genes as is the heart, nervous system, immune system and many other organs and tissues. T‐box gene loss‐of‐function mutations in humans cause major developmental syndromes such as ulnar‐mammary and Holt–Oram syndrome, and other abnormalities are increasingly being attributed to alteration in T‐box gene function, including the association with many types of cancer.

Key Concepts

  • T‐box genes code for transcription factors with diverse roles in development through regulation of a variety of downstream target genes.
  • They comprise an ancient gene family present in all metazoans as well as nonmetazoan lineages, defined by a conserved DNA‐binding motif.
  • In vertebrates, T‐box genes play diverse and key roles in specification, differentiation and development of most organ systems.
  • Mutations in T‐box genes result in complex birth defects and/or neonatal lethality and usually show effects in heterozygotes and homozygotes.
  • Multiple tissues may be affected by the same T‐box gene, and multiple T‐box genes may affect the same tissue at the same or different times in development.
  • Mutation or misregulation of T‐box genes is associated with a large variety of human cancers.
  • Little information is available about the role of T‐box genes in adult organisms.

Keywords: T‐box genes; Tbx; transcription factors; development; organogenesis; birth defects; gene family; evolution; stem cells; cancer

Figure 1. Phylogenetic tree of the T‐box gene family in vertebrates. The tree is based on phylogenetic analysis of the amino acid sequences of the T‐box domain, the DNA (deoxyribonucleic acid)‐binding motif that spans 180–200 amino acid residues and binds DNA in a sequence‐specific manner (Papaioannou, ; Papaioannou and Goldin, ). Subfamilies are indicated by the brackets on the left, although further subdivisions into subclasses are possible (Sebé‐Pedrós and Ruiz‐Trillo, ). All genes shown are represented in human and mouse with the exception of the zebrafish genes Drtbx16, which is present in zebrafish, birds and frogs (called VegT), but not mammals, and Drtbx6. The zebrafish gene Drtbx24 (not shown), rather than Drtbx6, is the orthologue of mammalian Tbx6, and it has thus been suggested that Drtbx6 be renamed Drtbx26. The gene duplication of T in Xenopus to form Xbra and Xbra3 is not shown. Common synonyms are indicated after the slash.
Figure 2. The evolution of expression and function in the Tbr1 gene subfamily. Inferred character states for the evolution of developmental functions by the Eomes/Tbr1/Tbx21 genes have been mapped to a phylogenetic species tree of selected groups. Gene duplication events indicating the birth of Tbx21 and the Eomes/Tbr1 protogene and then Eomes and Tbr1 are shown in bold. Branch lengths are not to scale. Adapted and reproduced with permission from Horton and Gibson‐Brown 2002 © John Wiley and Sons.
Figure 3. The expression domains of T‐box genes during mouse preimplantation and early postimplantation development. Eomes (yellow) is expressed in the TE layer of the blastocyst and after implantation is expressed in the extraembryonic ectoderm (ExE) and later the chorion, the visceral endoderm (VE), including AVE, and the posterior proximal epiblast. Tbx3 (green) is expressed in the ICM of the preimplantation embryo and later in the extraembryonic endoderm of the developing yolk sac. Mga (blue stripes) is also expressed in the ICM and then in the epiblast of the postimplantation embryo. T (red stripes) is expressed in the posterior epiblast and ExE and later in the core of the allantois, the primitive streak and node. Tbx6 (blue) overlaps T in the primitive streak but is not expressed in the node. Tbx4 (purple) is expressed in the allantois. AVE, anterior visceral endoderm; EPC, ectoplacental cone; ExE, extraembryonic ectoderm; ExEn, extraembryonic endoderm; ICM, inner cell mass; TE, trophectoderm; VE, visceral endoderm.
Figure 4. The expression domains of T‐box genes during heart development. T‐box genes are expressed in complex, overlapping patterns throughout heart development. The E8.25 heart is shown in a left lateral view of the whole embryo and in a frontal view of the isolated heart and second heart field (SHF). Hearts at later stages are shown as schematic transverse sections. Colour coding indicates the expression of individual genes or combinations of genes in different regions. AVC, atrioventricular canal; IFT, inflow tract; IVS, interventricular septum; LA, left atrium; LSH, left sinus horn; LV, left ventricle; OFT, outflow tract; RSH, right sinus horn; RV, right ventricle; SHF, second heart field; V, ventricle and VV, venous valves. Reproduced with permission from Greulich et al. 2011 © Oxford University Press.
Figure 5. Expression of Tbx2 at midgestation and the oncogenic roles of human TBX2. (a) In situ hybridisation at embryonic day (E) 9.5 shows that Tbx2 is expressed in multiple tissues and organ primordia including the dorsal retina (dr), both the outflow tract (oft) and atrioventricular canal (avc) of the heart, the margins of the forelimb buds (fl) and later the hindlimbs (not yet visible), the mesenchyme of the branchial arches (ba), the otic vesicles (ov), the Wolffian ducts (Wd) and ventral region corresponding to the future genital tubercle (gt) (Douglas et al., ) and the developing mammary glands (not yet visible). (b) The oncogenic roles of TBX2 mediated through its known cofactors and target genes are indicated. Upregulation of TBX2 affects EMT through upregulation of mesenchymal proteins and downregulation of epithelial markers and is associated with an increased ability of cells to invade and migrate (left side of diagram). TBX2 is also a potent growth‐promoting factor owing to its ability to bypass senescence and repress negative regulators of the cell cycle (right side of diagram). Reproduced from Biochimica et Biophysica Acta 1846, Wansleben et al., T‐box transcription factors in cancer biology. 380–391, 2014 © Elsevier.
Figure 6. Summary of major areas of T‐box gene function in mammals. Filled squares indicate a known function in the development of the tissues or organs indicated. Gene subfamilies are colour coded. For details, see text and Table.


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Further Reading

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Papaioannou, Virginia E(Jul 2017) T‐Box Genes: Developmental Functions in Mammals. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026975]