|, T, brachyury homolog (mouse), SAVA, TFT, T brachyury transcription factor, T-box transcription factor T, T|
Brachyury is a protein that in humans is encoded by the TBXT gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.
The brachyury mutation was first described in mice by Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous animals. In homozygous animals the brachyury mutation is lethal at around embryonic day 10 due to defects in mesoderm formation, notochord differentiation and the absence of structures posterior to the forlimb bud (Dobrovolskaïa-Zavadskaïa, 1927). The name brachyury comes from the Greek brakhus meaning short and oura meaning tail.
In 2018 HGNC updated the human gene name from T to TBXT, presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course.
The mouse T gene was cloned by Bernhard Herrmann and colleagues and proved to encode a 436 amino acid embryonic nuclear transcription factor. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. T is the founding member of the T-box family which in mammals currently consists of 18 T-box genes.
The gene brachyury appears to have a conserved role in defining the midline of a bilaterian organism, and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs. Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore. It also defines the mesoderm during gastrulation. Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.
Brachyury has also been shown to help establish the cervical vertebral blueprint during fetal development. The number of cervical vertebrae is highly conserved among all mammals; however a spontaneous vertebral and spinal dysplasia (VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven.
In mice T is expressed in the inner cell mass of the blastocyst stage embryo (but not in the majority of mouse embryonic stem cells) followed by the primitive streak (see image). In later development expression is localised to the node and notochord.
In Xenopus laevis Xbra (the Xenopus T homologue, also recently renamed t) is expressed in the mesodermal marginal zone of the pre-gastrula embryo followed by localisation to the blastopore and notochord at the mid-gastrula stage.
The Danio rerio homologue is known as ntl (no tail)
Expression of the brachyury gene has been identified as a definitive diagnostic marker of chordoma, a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. Furthermore, germ line duplication of brachyury confers major susceptibility to chordoma. The chromosomal region on 6q27 containing the brachyury gene was gained in 6 of 21 chordomas (29%), and none of the 21 chordomas analyzed showed deletions that could have affected this gene.
Brachyury is an important factor in promoting the epithelial-mesenchymal transition (EMT). Cells that over-express brachyury have down-regulated expression of the adhesion molecule E-cadherin, which allows them to undergo EMT. This process is at least partially mediated by the transcription factors AKT and Snail.
Overexpression of brachyury has been linked to Hepatocellular carcinoma (HCC, also called malignant hepatoma), a common type of liver cancer. While brachyury is promoting EMT, it can also induce metastasis of HCC cells. Brachyury expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.
Brachyury is overexpressed in a number of tumor types.
- GRCh38: Ensembl release 89: ENSG00000164458 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000062327 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Entrez Gene: T".
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- Le Gouar, M.; Guillou, A.; Vervoort, M. (2004). "Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc Patella vulgata". Development genes and evolution. 214 (5): 250–256. doi:10.1007/s00427-004-0399-z. PMID 15034714.
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- Turner, David A; Rué, Pau; Mackenzie, Jonathan P; Davies, Eleanor; Arias, Alfonso Martinez (2014-08-13). "Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells". BMC Biology. 12 (1). doi:10.1186/s12915-014-0063-7. PMC 4171571. PMID 25115237.
- Kromik A, Ulrich R, Kusenda M, et al. The mammalian cervical vertebrae blueprint depends on the T (brachyury) Gene. Genetics. 2015;199(3):183+. doi:10.1534/genetics.114.169680.
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- Du R, Wu S, Lv H, et al. Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Exp Clin Canc Res. 2014;33:105. doi: 10.1186/s13046-014-0105-6.
- Sun SR, Sun WJ, Xia L, et al. The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression. J Cell Commun Signal. 2014; 12:76. doi:10.1186/s12964-014-0076-4.
- Yoshikawa T, Piao Y, Zhong J, Matoba R, Carter MG, Wang Y, Goldberg I, Ko MS (January 2006). "High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridization". Gene Expr. Patterns. 6 (2): 213–24. doi:10.1016/j.modgep.2005.06.003. PMC 1850761. PMID 16325481.
- Meisler (1997). "Mutation watch: Mouse brachyury (T), the T-box gene family, and human disease".
- Mouse Genome Informatics entry for T
- European Bioinformatics Institute InterPro entry for Brachyury
- Information Hyperlinked Over Proteins entry for Brachyury
- Xenbase Gene entry for t
- Human T genome location and T gene details page in the UCSC Genome Browser.