T‐Box Genes: Developmental Functions in Mammals

Abstract

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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References

Arnold JS, Werling U, Braunstein EM, et al. (2006) Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Development 133: 977–987.

Arnold SJ, Hofmann UK, Bikoff EK and Robertson EJ (2008a) Pivotal roles for eomesodermin during axis formation, epithelium‐to‐mesenchyme transition and endoderm specification in the mouse. Development 135: 501–511. DOI: 10.1242/dev.014357.

Arnold SJ, Huang GJ, Cheung AFP, et al. (2008b) The T‐box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone. Genes & Development 22: 2479–2484. DOI: 10.1101/gad.475408.

Arora R, del Alcazar CM, Morrisey EE, Naiche LA and Papaioannou VE (2012a) Candidate gene approach identifies multiple genes and signaling pathways downstream of Tbx4 in the developing allantois. PLoS One 7: e43581.

Arora R, Metzger R and Papaioannou VE (2012b) Multiple roles and interactions of Tbx4 and Tbx5 in the development of the respiratory system. PLoS Genetics 8: e1002866.

Begum S and Papaioannou VE (2011) Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas. Gene Expression Patterns 11: 476–483.

Behesti H, Papaioannou VE and Sowden J (2009) Loss of Tbx2 delays optic vesicle invagination leading to small optic cups. Developmental Biology 333: 360–372.

Bulfone A, Wang F, Hevner R, et al. (1998) An olfactory sensory map develops in the absence of normal projection neurons or GABAergic interneurons. Neuron 21: 1273–1282.

Cai X, Nomura‐Kitabayashi A, Cai W, et al. (2011) Myocardial Tbx20 regulates early atrioventricular canal formation and endocardial epithelial‐mesenchymal transition via Bmp2. Developmental Biology 360: 381–390.

Chapman DL and Papaioannou VE (1998) Three neural tubes in mouse embryos with mutations in the T‐box gene, Tbx6. Nature 391: 695–697.

Chen T, Heller E, Beronja S, et al. (2012) An RNA interference screen uncovers a new molecule in stem cell self renewal and long‐term regeneration. Nature 485: 104–108.

Concepcion D and Papaioannou VE (2014) Nature and extent of left/right axis defects in TWis/TWis mutant embryos. Developmental Dynamics 243: 1046–1053.

Costello I, Pimeisl IM, Drager S, et al. (2011) The T‐box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. Nature Cell Biology 13: 1084–1091. DOI: 10.1038/ncb2304.

Dobrovolskaïa‐Zavadskaïa N (1927) Sur la mortification spontanée de la queue che la souris nouveau‐née et sur l'existence d'un caractère (facteur) héréditaire "non viable". Comptes rendus des séances de la Société de biologie et de ses filiales 97: 114–116.

Douglas NC, Heng K, Sauer MV and Papaioannou VE (2012) Dynamic expression of Tbx2 subfamily genes in development of the mouse reproductive system. Developmental Dynamics 241: 365–375.

Douglas NC and Papaioannou VE (2013) The T‐box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. Journal of Mammary Gland Biology and Neoplasia 18: 143–147.

Drouin J (2016) 60 YEARS OF POMC: transcriptional and epigenetic regulation of POMC gene expression. Journal of Molecular Endocrinology 56: T99–T112. DOI: 10.1530/jme-15-0289.

Duboc V and Logan MPO (2011) Regulation of limb bud initiation and limb‐type morphology. Developmental Dynamics 240: 1017–1027.

Greulich F, Rudat C and Kispert A (2011) Mechanisms of T‐box gene function in the developing heart. Cardiovascular Research 91: 212–222.

Hadjantonakis A‐K, Pisano E and Papaioannou VE (2008) Tbx6 regulates left/right patterning in mouse embryos through effects on nodal cilia and perinodal signaling. PLoS One 3: e2511.

Hariri F, Nemer M and Nemer G (2012) T‐box factors: insights into the evolutionary emergence of the complex heart. Annals of Medicine 44: 680–693. DOI: 10.3109/07853890.2011.607468.

Horton AC and Gibson‐Brown JJ (2002) Evolution of developmental functions by the Eomesodermin, T‐brain‐1, Tbx21 subfamily of T‐box genes: insights from Amphioxus. Journal of Experimental Zoology 294: 112–121.

Horton AC, Mahadevan NR, Minguillon C, et al. (2008) Conservation of linkage and evolution of developmental fucntion within the Tbx2/3/4/5 subfamily of T‐box genes: implications for the origin of vertbrate limbs. Development Genes and Evolution 218: 613–628.

Huang TN, Chuang HC, Chou WH, et al. (2014) Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nature Neuroscience 17: 240–247. DOI: 10.1038/nn.3626.

Inman KE and Downs KM (2007) The murine allantois: emerging paradigms in development of the mammalian umbilical cord and its relation to the fetus. Genesis 45: 237–258.

Kelly RG, Jerome‐Majewska LA and Papaioannou VE (2004) The del 22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis. Human Molecular Genetics 13: 2829–2840.

King M, Arnold JS, Shanske A and Morrow BE (2006) T‐genes and limb bud development. American Journal of Medical Genetics. Part A 140: 1407–1413. DOI: 10.1002/ajmg.a.31250.

Lazarevic V, Glimcher LH and Lord GM (2013) T‐bet: a bridge between innate and adaptive immunity. Nature Reviews. Immunology 13: 777–789.

Mao CA, Li H, Zhang Z, et al. (2014) T‐box transcription regulator Tbr2 is essential for the formation and maintenance of Opn4/melanopsin‐expressing intrinsically photosensitive retinal ganglion cells. Journal of Neuroscience 34: 13083–13095. DOI: 10.1523/jneurosci.1027-14.2014.

Mesbah K, Rana MS, Francou A, et al. (2012) Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis. Human Molecular Genetics 21: 1217–1229.

Minguillon C, Gibson‐Brown JJ and Logan MP (2009) Tbx4/5 gene duplication and the origin of vertebrate paired appendages. Proceedings of the National Academy of Sciences of the United States of America 106: 21726–21730. DOI: 10.1073/pnas.0910153106.

Niwa H, Ogawa K, Shimosato D and Adachi K (2009) A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460: 118–122. DOI: 10.1038/nature08113.

Nowotschin S, Costello I, Piliszek A, et al. (2013) The T‐box transcription factor Eomesodermin is essential for AVE induction in the mouse embryo. Genes & Development 27: 997–1002. DOI: 10.1101/gad.215152.113.

Papaioannou VE (2001) T‐box genes in development: from hydra to humans. International Review of Cytology 207: 1–70.

Papaioannou VE and Goldin SN (2008) Introduction to the T‐box genes and their roles in developmental signaling pathways. In: Epstein CJ, Erickson RP and Wynshaw‐Boris A (eds) Inborn Errors of Development. The Molecular Basis of Clinical Disorders of Morphogenesis, 2nd edn, pp. 852–861. Oxford, UK: Oxford University Press.

Papaioannou VE (2014) The T‐box gene family: emerging roles in development, stem cells and cancer. Development 141: 3819–3833. DOI: 10.1242/dev.104471.

Papangeli I and Scambler P (2013) The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdisciplinary Reviews: Developmental Biology 2: 393–403. DOI: 10.1002/wdev.75.

Parisot P, Mesbah K, Theveniau‐Ruissy M and Kelly RG (2011) Tbx1, subpulmonary myocardium and conotruncal congenital heart defects. Birth Defects Research. Part A, Clinical and Molecular Teratology 91: 477–484. DOI: 10.1002/bdra.20803.

Roybon L, Deierborg T, Brundin P and Li JY (2009) Involvement of Ngn2, Tbr and NeuroD proteins during postnatal olfactory bulb neurogenesis. The European Journal of Neuroscience 29: 232–243. DOI: 10.1111/j.1460-9568.2008.06595.x.

Russ AP, Wattler S, Colledge WH, et al. (2000) Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404: 95–98.

Sebé‐Pedrós A, Ariza‐Cosano A, Weirauch MT, et al. (2013) Early evolution of the T‐box transcription factor family. PNAS 110: 16050–16055.

Sebé‐Pedrós A and Ruiz‐Trillo I (2017) Evolution and classification of the T‐Box transcription factor family. Current Topics in Developmental Biology 122: 1–26.

Shen T, Aneas I, Sakabe N, et al. (2011) Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. Journal of Clinical Investigation 121: 4640–4654. DOI: 10.1172/JCI59472.

Song MR, Shirasaki R, Cai CL, et al. (2006) T‐Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body migration. Development 133: 4945–4955. DOI: 10.1242/dev.02694.

Strumpf D, Mao CA, Yamanaka Y, et al. (2005) Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132: 2093–2102. DOI: 10.1242/dev.01801.

Takemoto T, Uchikawa M, Yoshida M, et al. (2011) Tbx6‐dependent regulation of Sox2 regulation determines neural vs mesodermal fate of axial stem cells. Nature 470: 394–398.

Tanaka M (2013) Molecular and evolutionary basis of limb field specification and limb initiation. Development, Growth & Differentiation 55: 149–163. DOI: 10.1111/dgd.12017.

Vivante A, Kleppa MJ, Schulz J, et al. (2015) Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development. American Journal of Human Genetics 97: 291–301. DOI: 10.1016/j.ajhg.2015.07.001.

Wansleben S, Peres J, Hare S, Goding CR and Prince S (2014) T‐box transcription factors in cancer biology. Biochimica et Biophysica Acta 1846: 380–391. DOI: 10.1016/j.bbcan.2014.08.004.

Washkowitz AJ, Schall C, Zhang K, et al. (2015) Mga is essential for the survival of pluripotent cells during peri‐implantation development. Development 142: 31–40. DOI: 10.1242/dev.111104.

Wu SP, Dong XR, Regan JN, Su C and Majesky MW (2013) Tbx18 regulates development of the epicardium and coronary vessels. Developmental Biology 383: 307–320. DOI: 10.1016/j.ydbio.2013.08.019.

Wu N, Ming X, Xiao J, et al. (2015) TBX6 null variants and a common hypomorphic allele in congenital scoliosis. The New England Journal of Medicine 372: 341–350. DOI: 10.1056/NEJMoa1406829.

Zirzow S, Ludtke TH, Brons JF, et al. (2009) Expression and requirement of T‐box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse. Developmental Biology 336: 145–155. DOI: 10.1016/j.ydbio.2009.09.020.

Further Reading

Chen W, Liu J, Yuan D, et al. (2016) Progress and perspective of TBX6 gene in congenital vertebral malformations. Oncotarget. DOI: 10.18632/oncotarget.10619.

Frasch M (2017) T‐box genes in development and disease. Current Topics in Developmental Biology 122: 2–426. ISBN: 978-0-12-801380-9.

Gao S, Li X and Amendt BA (2013) Understanding the role of Tbx1 as a candidate gene for 22q11.2 deletion syndrome. Current Allergy and Asthma Reports 13: 613–621. DOI: 10.1007/s11882-013-0384-6.

Huang TN and Hsueh YP (2015) Brain‐specific transcriptional regulator T‐brain‐1 controls brain wiring and neuronal activity in autism spectrum disorders. Frontiers in Neuroscience 9: 406. DOI: 10.3389/fnins.2015.00406.

Naiche LA, Harrelson Z, Kelly RG and Papaioannou VE (2005) T‐box genes in vertebrate development. Annual Review of Genetics 39: 219–239.

Nibu Y, Jose‐Edwards DS and Di Gregorio A (2013) From notochord formation to hereditary chordoma: the many roles of Brachyury. BioMed Research International 2013: 826435. DOI: 10.1155/2013/826435.

Pflugfelder GO (2009) omb and circumstance. Journal of Neurogenetics 23: 15–33. DOI: 10.1080/01677060802471619.

Pocock R, Ahringer J, Mitsch M, Maxwell S and Woollard A (2004) A regulatory network of T‐box genes and the even‐skipped homologue vab‐7 controls patterning and morphogenesis in C. elegans. Development 131: 2373–2385. DOI: 10.1242/dev.01110.

Sylva M, van den Hoff MJ and Moorman AF (2014) Development of the human heart. American Journal of Medical Genetics. Part A 164a: 1347–1371. DOI: 10.1002/ajmg.a.35896.

Takashima Y and Suzuki A (2013) Regulation of organogenesis and stem cell properties by T‐box transcription factors. Cellular and Molecular Life Sciences 70: 3929–3945. DOI: 10.1007/s00018-013-1305-5.

Tickle C (2015) How the embryo makes a limb: determination, polarity and identity. Journal of Anatomy 227: 418–430. DOI: 10.1111/joa.12361.

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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]