Brachyury

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T brachyury transcription factor
PDB 1xbr EBI.jpg
PDB rendering based on 1xbr.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols T ; SAVA; TFT
External IDs OMIM601397 MGI98472 HomoloGene2393 GeneCards: T Gene
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 [1] [2]

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[edit]

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[edit]

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]

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.[8]

Expression[edit]

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[edit]

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.[9] 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[10] and Snail.[11]

Overexpression of brachyury has been linked to hepatocellular carnicoma (HCC), 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.[10]

Additionally, overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis.[11]

Brachyury is overexpressed in a number of tumor types.

See also[edit]

References[edit]

  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. ^ a b c 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. ^ 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.
  9. ^ 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. 
  10. ^ a b 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.
  11. ^ a b 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[edit]

External links[edit]