T-box refers to a group oftranscription factors involved inembryoniclimb andheart development.[1] Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.[2]
T-boxes are especially important to the development of embryos, found inzebrafish oocyte by Bruce et al 2003 andXenopus laevis oocyte by Xanthos et al 2001. They are alsoexpressed in later stages, including adultmouse andrabbit studied by Szabo et al 2000.[3]
Mutations in the first one found caused short tails in mice, and thus the protein encoded was namedbrachyury, Greek for "short-tail". In mice this gene is namedTbxt, and in humans it is namedTBXT.[4][5] Brachyury has been found in allbilaterian animals that have been screened, and is also present in thecnidaria.[6]
The mouseTbxt gene was cloned[7] and found to be a 436 amino acid embryonic nucleartranscription factor. The protein brachyury binds to the T-box through a region at its N-terminus.
The encoded proteins ofTBX5 andTBX4 play a role inlimb development, and play a major role inlimb bud initiation specifically.[8] For instance, in chickens TBX4 specifies hindlimb status while Tbx5 specifies forelimb status.[9] The activation of these proteins byHox genes initiates signaling cascades that involve theWnt signaling pathway andFGF signals in limb buds.[8] Ultimately, TBX4 and TBX5 lead to the development ofapical ectodermal ridge (AER) andzone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.[8] Together, TBX5 and TBX4 play a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[10]
In humans, and some other animals, defects in theTBX5gene expression are responsible forHolt–Oram syndrome, which is characterized by at least one abnormalwrist bone. Other arm bones are almost always affected, though the severity can vary widely, from complete absence of a bone, to only a reduction in bone length.[11][12] Seventy-five percent of affected individuals also haveheart defects, most often there is no separation between the left and rightventricle of theheart.[13]
TBX3 is associated withulnar–mammary syndrome in humans, but is also responsible for the presence or absence ofdun color in horses, and has no deleterious effects whether expressed or not.[14]
^Scholz CB, Technau U (January 2003). "The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa)".Development Genes and Evolution.212 (12):563–70.doi:10.1007/s00427-002-0272-x.PMID12536320.S2CID25311702.
^"Holt–Oram syndrome".Genetics Home Reference. U.S. National Library of Medicine. June 2014. Retrieved18 April 2018.
^McDermott DA, Fong JC, Basson CT. Holt–Oram Syndrome. 2004 Jul 20 [Updated 2015 Oct 8]. In Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:https://www.ncbi.nlm.nih.gov/books/NBK1111/
^Bossert, T; Walther, T; Gummert, J; Hubald, R; Kostelka, M; Mohr, FW (October 2002). "Cardiac malformations associated with the Holt–Oram syndrome—report on a family and review of the literature".The Thoracic and Cardiovascular Surgeon.50 (5):312–4.doi:10.1055/s-2002-34573.PMID12375192.S2CID19665997.
