Brachyury

T brachyury transcription factor
PDB rendering based on 1xbr.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1xbr​
Identifiers
Symbols	T ; SAVA; TFT
External IDs	OMIM: 601397 MGI: 98472 HomoloGene: 2393 GeneCards: T Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II distal enhancer sequence-specific DNA binding • RNA polymerase II transcription factor binding • RNA polymerase II activating transcription factor binding • transcriptional repressor activity, RNA polymerase II transcription factor binding • transcription factor activity, sequence-specific DNA binding • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Cellular component • nuclear chromatin • nucleus • cytoplasm Biological process • negative regulation of transcription from RNA polymerase II promoter • vasculogenesis • somitogenesis • neural plate morphogenesis • neural tube closure • heart morphogenesis • positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation • transcription, DNA-templated • signal transduction • penetration of zona pellucida • mesoderm development • mesoderm migration involved in gastrulation • positive regulation of cell proliferation • anterior/posterior axis specification, embryo • notochord formation • signal transduction involved in regulation of gene expression • BMP signaling pathway • post-anal tail morphogenesis • embryonic skeletal system development • canonical Wnt signaling pathway • bone morphogenesis • SMAD protein signal transduction • determination of heart left/right asymmetry • cellular response to retinoic acid • primitive streak formation Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6862	20997
Ensembl	ENSG00000164458	ENSMUSG00000062327
UniProt	O15178	P20293
RefSeq (mRNA)	NM_001270484	NM_009309
RefSeq (protein)	NP_001257413	NP_033335
Location (UCSC)	Chr 6: 166.16 – 166.17 Mb	Chr 17: 8.43 – 8.44 Mb
PubMed search

Brachyury is a protein that in humans is encoded by the T gene.^[1][2] Brachyury is a transcription factor within the T-box complex of genes.^[3] It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.^[3]

History

The brachyury mutation was first described in mice by Nadine Dobrovolskaïa-Zavadskaïa 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.

According to human and mouse genome nomenclature, brachyury now has the symbol and gene name T although brachyury is maintained as the gene description.

The mouse T gene was cloned by Bernhard Herrmann and colleagues^[4] and proved to encode an 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.

Brachyury expression in 7.5dpc CD1 mouse embryos

Function

The gene brachyury appears to have a conserved role in defining the midline of a bilaterian organism,^[5] and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.^[6] Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore.^[3] It also defines the mesoderm during gastrulation.^[7] Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.^[8][9]

Transcription of genes required for mesoderm formation and cellular differentiation.

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.^[10]

Expression

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)

Cancer

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.^[11] 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^[12] and Snail.^[13]

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.^[12]

Additionally, overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis.^[13]

Brachyury is overexpressed in a number of tumor types.

See also

• Homeobox protein NANOG
• POU5F1
• SOX2
• MIXL1
• GSC
• EOMES
• Transcription factors
• Gene regulatory network
• Bioinformatics
• Chordoma

References

1. "Entrez Gene: T".
2. Edwards YH, Putt W, Lekoape KM, Stott D, Fox M, Hopkinson DA, Sowden J (March 1996). "The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27". Genome Res. 6 (3): 226–33. doi:10.1101/gr.6.3.226. PMID 8963900.
3. Scholz CB, Technau U (January 2003). "The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa)". Dev. Genes Evol. 212 (12): 563–70. doi:10.1007/s00427-002-0272-x. PMID 12536320.
4. Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H (February 1990). "Cloning of the T gene required in mesoderm formation in the mouse". Nature 343 (6259): 617–22. doi:10.1038/343617a0. PMID 2154694.
5. 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.
6. Lartillot, N; Lespinet, O; Vervoort, M; Adoutte, A (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): 1411–1421. PMID 11880350.
7. Marcellini, S.; Technau, U.; Smith, J.; Lemaire, P. (2003). "Evolution of Brachyury proteins: identification of a novel regulatory domain conserved within Bilateria". Developmental Biology 260 (2): 352–361. doi:10.1016/S0012-1606(03)00244-6. PMID 12921737.
8. Hashimoto, K.; Fujimoto, H.; Nakatsuji, N. (1987-08-01). "An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells". Development 100 (4): 587–598. ISSN 0950-1991. PMID 3327671.
9. 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.
10. 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.
11. 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". J. Pathol. 209 (2): 157–65. doi:10.1002/path.1969. PMID 16538613.
12. 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.
13. 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.

Further reading

• 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." (PDF).

External links

• 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