Gene transcriptions/Boxes/Ts

Tiktaalik, a tetrapodomorph with wrists, straddles the fish-tetrapod divide. Credit: Esv, derivative Petter Bøckman.

T-box refers to a group of transcription factors involved in limb and heart development.

The encoded proteins of Tbx5 and Tbx4 play a role in limb development, and play a major role in limb bud initiation specifically. For instance, in chickens Tbx4 specifies hindlimb status while Tbx5 specifies forelimb status. The activation of these proteins by Hox genes initiates signaling cascades that involve the Wnt signaling pathway and fibroblast growth factor (FGF) signals in limb buds. Ultimately, Tbx4 and Tbx5 lead to the development of the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb. Together, Tbx5 and Tbx4 play a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.

TBX3 is associated with ulnar-mammary syndrome in humans, but is also responsible for the presence or absence of dun color in horses, and has no deleterious effects whether expressed or not.

Conserved Protein Domain Family

"The T-box family is an ancient group that appears to play a critical role in development in all animal species. These genes were uncovered on the basis of similarity to the DNA binding domain of murine Brachyury (T) gene product, the defining feature of the family. Common features shared by T-box family members are DNA-binding and transcriptional regulatory activity, a role in development and conserved expression patterns, most of the known genes in all species being expressed in mesoderm or mesoderm precursors."

Human genes

Gene ID: 6862 is TBXT T-box transcription factor T. "The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation. The protein is localized to notochord-derived cells. Variation in this gene was associated with susceptibility to neural tube defects and chordoma. A mutation in this gene was found in a family with sacral agenesis with vertebral anomalies."

1. NP_003172.1 T-box transcription factor T isoform 1.
2. NP_001257413.1 T-box transcription factor T isoform 2.
3. NP_001353214.1 T-box transcription factor T isoform 3.
4. NP_001353215.1 T-box transcription factor T isoform 3.
5. XP_011534382.1 brachyury protein isoform X1.

Gene ID: 6899 is TBX1 T-box 1. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene."

1. NP_542377.1 T-box transcription factor TBX1 isoform A.
2. NP_005983.1 T-box transcription factor TBX1 isoform B.
3. NP_542378.1 T-box transcription factor TBX1 isoform C.
4. XP_016884414.1 T-box transcription factor TBX1 isoform X1.
5. XP_006724375.1 T-box transcription factor TBX1 isoform X2.
6. XP_016884415.1 T-box transcription factor TBX1 isoform X2.
7. XP_016884416.1 T-box transcription factor TBX1 isoform X3.
8. XP_016884417.1 T-box transcription factor TBX1 isoform X4.

Gene ID: 6909 is TBX2 T-box 2. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene."

Gene ID: 6910 is TBX5 T-box 5. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene."

1. NP_000183.2 T-box transcription factor TBX5 isoform 1 (variant 1).

1. NP_542448.1 T-box transcription factor TBX5 isoform 3 (variant 3).
2. NP_852259.1 T-box transcription factor TBX5 isoform 1 (variant 4).
3. XP_016875401.1 T-box transcription factor TBX5 isoform X1.

Gene ID: 6911 is TBX6 T-box 6. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures."

1. NP_004599.2 T-box transcription factor TBX6.
2. XP_005255580.1 T-box transcription factor TBX6 isoform X1.
3. XP_011544228.1 T-box transcription factor TBX6 isoform X1.
4. XP_016879103.1 T-box transcription factor TBX6 isoform X1.
5. XR_950840.3 RNA Sequence, transcript variant X4, misc RNA.

Gene ID: 6913 is TBX15 T-box 15. "This gene belongs to the T-box family of genes, which encode a phylogenetically conserved family of transcription factors that regulate a variety of developmental processes. All these genes contain a common T-box DNA-binding domain. Mutations in this gene are associated with Cousin syndrome."

1. NP_001317606.1 T-box transcription factor TBX15 isoform 1.
2. NP_689593.2 T-box transcription factor TBX15 isoform 2.
3. XP_005271218.1 T-box transcription factor TBX15 isoform X1.
4. XP_011540354.1 T-box transcription factor TBX15 isoform X2.

Gene ID: 6926 is TBX3 T-box 3. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This protein is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. Mutations in this gene cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair, and genital development. Alternative splicing of this gene results in three transcript variants encoding different isoforms; however, the full length nature of one variant has not been determined."

1. NP_005987.3 T-box transcription factor TBX3 isoform 1.
2. NP_057653.3 T-box transcription factor TBX3 isoform 2.

Gene ID: 9095 is TBX19 T-box 19. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene were found in patients with isolated deficiency of pituitary POMC-derived ACTH, suggesting an essential role for this gene in differentiation of the pituitary POMC lineage. ACTH deficiency is characterized by adrenal insufficiency symptoms such as weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure."

Gene ID: 9096 is TBX18 T-box 18. "This genes codes for a member of an evolutionarily conserved family of transcription factors that plays a crucial role in embryonic development. The family is characterized by the presence of the DNA-binding T-box domain and is divided into five sub-families based on sequence conservation in this domain. The encoded protein belongs to the vertebrate specific Tbx1 sub-family. The protein acts as a transcriptional repressor by antagonizing transcriptional activators in the T-box family. The protein forms homo- or heterodimers with other transcription factors of the T-box family or other transcription factors."

1. NP_001073977.1 T-box transcription factor TBX18.
2. XP_016866961.1 T-box transcription factor TBX18 isoform X1.
3. XP_011534549.2 T-box transcription factor TBX18 isoform X2.
4. XP_011534550.2 T-box transcription factor TBX18 isoform X3.
5. XP_016866962.1 T-box transcription factor TBX18 isoform X4.
6. XP_011534551.2 T-box transcription factor TBX18 isoform X5.
7. XP_006715665.2 T-box transcription factor TBX18 isoform X6.

Gene ID: 9496 is TBX4 T-box 4. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity."

1. NP_001308049.1 T-box transcription factor TBX4 isoform 1.
2. NP_060958.2 T-box transcription factor TBX4 isoform 2.
3. XP_011523792.1 T-box transcription factor TBX4 isoform X1.
4. XP_011523793.1 T-box transcription factor TBX4 isoform X2.
5. XP_011523797.1 T-box transcription factor TBX4 isoform X3.

Gene ID: 10716 is TBR1 T-box, brain 1. "This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase."

Gene ID: 30009 is TBX21 T-box 21. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells."

Gene ID: 50945 is TBX22 T-box 22. "This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, Cleft palate with ankyloglossia, and it is believed to play a major role in human palatogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene."

1. NP_058650.1 T-box transcription factor TBX22 isoform 1.
2. NP_001103348.1 T-box transcription factor TBX22 isoform 1.
3. NP_001103349.1 T-box transcription factor TBX22 isoform 2.
4. NP_001290404.1 T-box transcription factor TBX22 isoform 2.

Gene ID: 57057 is TBX20 T-box 20. "This gene encodes a T-box family member. The T-box family members share a common DNA binding domain, termed the T-box, and they are transcription factors involved in the regulation of developmental processes. This gene is essential for heart development. Mutations in this gene are associated with diverse cardiac pathologies, including defects in septation, valvulogenesis and cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene."

1. NP_001071121.1 T-box transcription factor TBX20 isoform 1.
2. NP_001159692.1 T-box transcription factor TBX20 isoform 2.
3. XP_016867945.1 T-box transcription factor TBX20 isoform X1.

Gene ID: 347853 is TBX10 T-box 10, aka TBX7 and TBX13. "This gene encodes a member of the T-box family of transcription factors. These transcription factors share a DNA-binding domain called the T-box, and play a role in several developmental processes including early embryonic cell fate and organogenesis. The encoded protein is a member of the T-box 1 subfamily. Mutations in this gene are thought to be a cause of isolated cleft lip with or without cleft palate."

1. NP_005986.2 T-box transcription factor TBX10.
2. XP_011543295.1 T-box transcription factor TBX10 isoform X1.
3. XP_011543294.1 T-box transcription factor TBX10 isoform X2.

Consensus sequences

"The different inducing activities of Xbra, VegT and Eomesodermin suggest that the proteins might recognise different DNA target sequences. [...] All three proteins prove to recognise the same core sequence of TCACACCT with some differences in flanking nucleotides."

"Significantly, however, further rounds of selection tend to select repeats of the core sequence, and the spacing and orientation of the repeats are different for each protein. For example, as reported by Kispert and Herrmann (Kispert and Herrmann, 1993), Brachyury selects the palindromic sequence TCACACCTAGGTGTGA while Eomesodermin frequently selects two direct repeats of the core motif separated by four nucleotides. It is possible that differences such as these underlie the different effects of the different T box proteins."

"Previous work has shown that the sequence TCACACCT interacts with T box proteins (Casey et al., 1998; Casey et al., 1999; Kispert and Herrmann, 1993; Tada et al., 1998), and this motif, or variations of it, was observed in all the selected DNA fragments."

See also

• Gene transcription boxes