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 forelimb 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 crystal structure of the human brachyury protein was solved in 2017 by Opher Gileadi and colleagues at the Structural Genomics Consortium in Oxford.
Brachyury expression in 7.5dpc CD1 mouse embryos
Role in Development
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. It effects transcription of genes required for mesoderm formation and cellular differentiation.[clarification needed]
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 Xenopus laevisXbra (the XenopusT 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.
In breast cancer brachyury expression is associated with recurrence, metastasis and reduced survival. It is also associated with resistance to tamoxifen and to cytotoxic chemotherapy.
In lung cancer brachyury expression is associated with recurrence and decreased survival. It is also associated with resistance to cytotoxic chemotherapy, radiation, and EGFR kinase inhibitors.
In prostate cancer brachyury expression is associated with Gleason score, perineural, invasion and capsular invasion.
In addition to its role in common cancers, brachyury has been identified as a definitive diagnostic marker, key driver and therapeutic target for chordoma, a rare malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. The evidence regarding brachyury's role in chordoma includes:
Brachyury is highly expressed in all chordomas except for the dedifferentiated subtype, which accounts for less than 5% of cases
Germ line duplication of the brachyury gene is responsible for familial chordoma.
A germline SNP in brachyury is present in 97% of chordoma patients.
Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication.
Brachyury is the most selectively essential gene in chordoma relative to other cancer types.
Brachyury is associated with a large superenhancer in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor.
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.
Overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis.
Role as a therapeutic target
Because brachyury is expressed in tumors but not in normal adult tissues it has been proposed as a potential drug target with applicability across tumor types. In particular, brachyury-specific peptides are presented on HLA receptors of cells in which it is expressed, representing a tumor specific antigen. Various therapeutic vaccines have been developed which are intended to stimulate an immune response to brachyury expressing cells.
^Lartillot N, Lespinet O, Vervoort M, Adoutte A (March 2002). "Expression pattern of Brachyury in the mollusc Patella vulgata suggests a conserved role in the establishment of the AP axis in Bilateria". Development. 129 (6): 1411-21. PMID11880350.
^Shao C, Zhang J, Fu J, Ling F (November 2015). "The potential role of Brachyury in inducing epithelial-to-mesenchymal transition (EMT) and HIF-1? expression in breast cancer cells". Biochemical and Biophysical Research Communications. 467 (4): 1083-9. doi:10.1016/j.bbrc.2015.09.076. PMID26393908.
^Li K, Ying M, Feng D, Du J, Chen S, Dan B, et al. (December 2016). "Brachyury promotes tamoxifen resistance in breast cancer by targeting SIRT1". Biomedicine & Pharmacotherapy. 84: 28-33. doi:10.1016/j.biopha.2016.09.011. PMID27621036.
^Haro A, Yano T, Kohno M, Yoshida T, Koga T, Okamoto T, et al. (December 2013). "Expression of Brachyury gene is a significant prognostic factor for primary lung carcinoma". Annals of Surgical Oncology. 20 Suppl 3: S509-16. doi:10.1245/s10434-013-2914-9. PMID23456319. S2CID13383492.
^Shimamatsu S, Okamoto T, Haro A, Kitahara H, Kohno M, Morodomi Y, et al. (December 2016). "Prognostic Significance of Expression of the Epithelial-Mesenchymal Transition-Related Factor Brachyury in Intrathoracic Lymphatic Spread of Non-Small Cell Lung Cancer". Annals of Surgical Oncology. 23 (Suppl 5): 1012-1020. doi:10.1245/s10434-016-5530-7. hdl:2324/1866273. PMID27600618. S2CID2800270.
^Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM (June 2006). "Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas". The Journal of Pathology. 209 (2): 157-65. doi:10.1002/path.1969. PMID16538613. S2CID41440366.
^Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, et al. (November 2012). "A common single-nucleotide variant in T is strongly associated with chordoma". Nature Genetics. 44 (11): 1185-7. doi:10.1038/ng.2419. PMID23064415. S2CID38375774.