Developmental Signals - Tbx

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Introduction

Mouse forelimb Tbx5 expression.[1]
Mouse hindlimb Tbx4 expression.[1]

Brachyury was the first of this transcription factor family to be identified in mouse.[2] Genes in the TBX gene family provide instructions for making proteins called T-box proteins that play critical roles during embryonic development. These proteins are especially important for normal development of the arms, hands, and heart. T-box proteins regulate the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, T-box proteins are called transcription factors. Genes in the T-box family are grouped together because the proteins produced from these genes share a similar segment called a T box. The T box is the part of the protein that binds to DNA. T-box proteins often interact with one another or with other transcription factors that regulate gene activity.


Researchers have identified at least 17 genes in the T-box gene family. Mutations in these genes lead to disorders that involve the abnormal development of tissues in which a particular T-box gene is active (expressed). Many genetic disorders caused by T-box gene mutations are characterized by heart problems and/or skeletal abnormalities of the hands and arms.


(text from Genetics Home Reference http://ghr.nlm.nih.gov/geneFamily/tbx)


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

| Category:Tbx

Some Recent Findings

Pharyngeal arch segmentation model Tbx1 and Foxi3[3]
  • Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway[4] "Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung."
  • Tbx1 and Foxi3 genetically interact in the pharyngeal pouch endoderm in a mouse model for 22q11.2 deletion syndrome[3] "We investigated whether Tbx1, the gene for 22q11.2 deletion syndrome (22q11.2DS) and Foxi3, both required for segmentation of the pharyngeal apparatus (PA) to individual arches, genetically interact. We found that all Tbx1+/-;Foxi3+/- double heterozygous mouse embryos had thymus and parathyroid gland defects, similar to those in 22q11.2DS patients.... Several genes expressed in the PA epithelia were downregulated in both Tbx1 and Foxi3 null mutant embryos including Notch pathway genes Jag1, Hes1, and Hey1, suggesting that they may, along with other genes, act downstream to explain the observed genetic interaction. We found Alcam and Fibronectin extracellular matrix proteins were reduced in expression in Foxi3 null but not Tbx1 null embryos, suggesting that some, but not all of the downstream mechanisms are shared." OMIM - Tbx1 | OMIM - Foxi3
  • Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway[4] "Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung." respiratory
More recent papers  
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More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Tbx Embryology | Tbx Development | Tbx Gastrointestinal | Tbx Heart | Tbx Limb | Tbx Renal | 

Tbx Respiratory |


Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism[5] "Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism." muscle
  • Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a[6] "The pharyngeal pouches are a segmental series of epithelial structures that organize the embryonic vertebrate face. In mice and zebrafish that carry mutations in homologs of the DiGeorge syndrome gene TBX1, a lack of pouches correlates with severe craniofacial defects, yet how Tbx1 controls pouch development remains unclear. Using mutant and transgenic rescue experiments in zebrafish, we show that Tbx1 functions in the mesoderm to promote the morphogenesis of pouch-forming endoderm through wnt11r and fgf8a expression. Consistently, compound losses of wnt11r and fgf8a phenocopy tbx1 mutant pouch defects, and mesoderm-specific restoration of Wnt11r and Fgf8a rescues tbx1 mutant pouches. Time-lapse imaging further reveals that Fgf8a acts as a Wnt11r-dependent guidance cue for migrating pouch cells. We therefore propose a two-step model in which Tbx1 coordinates the Wnt-dependent epithelial destabilization of pouch-forming cells with their collective migration towards Fgf8a-expressing mesodermal guideposts."
  • Tbx1 regulates oral epithelial adhesion and palatal development[7] "Cleft palate, the most frequent congenital craniofacial birth defect, is a multifactorial condition induced by the interaction of genetic and environmental factors. In addition to complete cleft palate, a large number of human cases involve soft palate cleft and submucosal cleft palate. ...These findings suggest that Tbx1 regulates the balance between proliferation and differentiation of keratinocytes and is essential for palatal fusion and oral mucosal differentiation. The impaired adhesion separation of the oral epithelium together with compromised palatal mesenchymal growth is an underlying cause for various forms of cleft palate phenotypes in Tbx1(-/-) mice. Our present study reveals new pathogenesis of incomplete and submucous cleft palate during mammalian palatogenesis."

Human TBX Family

Table - Human Tbx Family
Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
TBX1 T-box 1 VCF CATCH22 22q11.21
TBX2 T-box 2 17q23.2
TBX3 T-box 3 UMS "TBX3-ISO, XHL" 12q24.21
TBX4 T-box 4 17q23.2
TBX5 T-box 5 HOS 12q24.21
TBX6 T-box 6 16p11.2
TBX10 T-box 10 TBX7 TBX13 11q13.2
TBX15 T-box 15 TBX14 1p12
TBX18 T-box 18 6q14.3
TBX19 T-box 19 "dj747L4.1, TPIT" 1q24.2
TBX20 T-box 20 7p14.2
TBX21 T-box 21 "TBLYM, T-bet" 17q21.32
TBX22 T-box 22 "CPX, CLPA" Xq21.1
TBX23P T-box 23, pseudogene TBX23 1q25
TBR1 T-box, brain 1 2q24.2
EOMES eomesodermin TBR2 3p24.1
MGA MGA, MAX dimerization protein "KIAA0518, MAD5, MXD5, FLJ12634" 15q15
TBXT T-box transcription factor T T 6q27
    Links: Developmental Signals - Tbx | OMIM Tbx3 | HGNC | Bmp Family | Sox Family | Tbx Family


Human TBX Family  
Table - Human Tbx Family
Approved
Symbol 		Approved Name Previous Symbols Synonyms Chromosome
TBX1 T-box 1 VCF CATCH22 22q11.21
TBX2 T-box 2 17q23.2
TBX3 T-box 3 UMS "TBX3-ISO, XHL" 12q24.21
TBX4 T-box 4 17q23.2
TBX5 T-box 5 HOS 12q24.21
TBX6 T-box 6 16p11.2
TBX10 T-box 10 TBX7 TBX13 11q13.2
TBX15 T-box 15 TBX14 1p12
TBX18 T-box 18 6q14.3
TBX19 T-box 19 "dj747L4.1, TPIT" 1q24.2
TBX20 T-box 20 7p14.2
TBX21 T-box 21 "TBLYM, T-bet" 17q21.32
TBX22 T-box 22 "CPX, CLPA" Xq21.1
TBX23P T-box 23, pseudogene TBX23 1q25
TBR1 T-box, brain 1 2q24.2
EOMES eomesodermin TBR2 3p24.1
MGA MGA, MAX dimerization protein "KIAA0518, MAD5, MXD5, FLJ12634" 15q15
TBXT T-box transcription factor T T 6q27
    Links: Developmental Signals - Tbx | OMIM Tbx3 | HGNC | Bmp Family | Sox Family | Tbx Family

Limb Development

Mouse- forelimb-bud-Tbx3-Tbx2.jpg

Mouse forelimb bud Tbx3 and Tbx2 expression[8]

Chicken limb gene expression 02.jpg

Chicken stage 21 wing bud[9]

Hindlimb Tbx2 model

Hindlimb Tbx2 model[10]


Links: Limb Development

Respiratory Development

Mouse respiratory Tbx4 and Tbx5.jpg Mouse respiratory Tbx4 and Tbx5 model[11]
  • A - Lung and trachea specification begins at E9.0 in the ventral foregut and at this time Tbx5 expression (light purple) is adjacent to the presumptive endoderm. Later, Tbx4 and Tbx5 expression (dark purple) is in mesenchyme associated with the lung and trachea. Tbx5 but not Tbx4 is important for specification of bilateral lung buds and the trachea.
  • B - Magnification of box shown in (A) representing the events in the growing tip during branching morphogenesis. Grey denotes epithelium and purple denotes mesenchyme. Tbx4 and Tbx5 interact with each other and act upstream of the Fgf10 signaling pathway. Decrease in Tbx4 and Tbx5 affects mesenchymal Fgf10 expression and expression of its targets in the epithelium – Bmp4, Spry2 and Etv5 – but not the expression of the epithelial Fgf10 receptor Fgfr2. In addition to Fgf10 expression in the mesenchyme, Tbx4 and Tbx5 also control the expression of an unknown factor(s) (X) that is essential for activation of the Fgf10 signaling pathway. Furthermore, Tbx4 and Tbx5 act upstream of Wnt2 in the mesenchyme.
  • C - In the trachea and the main stem bronchi Tbx4 and Tbx5 either control Sox9 expression, which in turn regulates cartilage condensation, or Tbx4 and Tbx5 regulate another factor (X) essential for chondrogenesis secondarily affecting Sox9 expression.

(Text from figure legend)

Links: Respiratory System Development

Heart Development

Tbx3 and Tbx18 are both involved with sinoatrial node development.

Cardiac conduction system[12] "Here, we assessed the genome-wide occupation of conduction system-regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo."

Gastrointestinal Development

Tbx1 and Tbx2 genes regulate foregut and pharyngeal development. Mutations in Tbx1 gene are associated with the foregut abnormality of oesophageal atresia with tracheo-oesophageal fistula (Q39.1).[13]

Links: Gastrointestinal Tract Development | Gastrointestinal_Tract_-_Oesophagus_Development#Abnormalities Oesophagus Abnormalities | OMIM - TBX1

Renal Development

Tbx18, Tbx1, Tbx2, Tbx3, and Tbx20 have various roles in renal development, see this recent review.[14]

  • TBX18 mutations associated with kidney and urinary tract anomalies - hydroureter (ureter dilation) and ureteropelvic junction obstruction.
Links: renal | OMIM - TBX18]

Muscle Development

Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism[5]

"Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism."


Links: muscle | OMIM - TBX15]

References

  1. ↑ 1.0 1.1 Taher L, Collette NM, Murugesh D, Maxwell E, Ovcharenko I & Loots GG. (2011). Global gene expression analysis of murine limb development. PLoS ONE , 6, e28358. PMID: 22174793 DOI.
  2. ↑ Korzh V & Grunwald D. (2001). Nadine Dobrovolskaïa-Zavadskaïa and the dawn of developmental genetics. Bioessays , 23, 365-71. PMID: 11268043 DOI.
  3. ↑ 3.0 3.1 Hasten E & Morrow BE. (2019). Tbx1 and Foxi3 genetically interact in the pharyngeal pouch endoderm in a mouse model for 22q11.2 deletion syndrome. PLoS Genet. , 15, e1008301. PMID: 31412026 DOI.
  4. ↑ 4.0 4.1 Karolak JA, Vincent M, Deutsch G, Gambin T, Cogné B, Pichon O, Vetrini F, Mefford HC, Dines JN, Golden-Grant K, Dipple K, Freed AS, Leppig KA, Dishop M, Mowat D, Bennetts B, Gifford AJ, Weber MA, Lee AF, Boerkoel CF, Bartell TM, Ward-Melver C, Besnard T, Petit F, Bache I, Tümer Z, Denis-Musquer M, Joubert M, Martinovic J, Bénéteau C, Molin A, Carles D, André G, Bieth E, Chassaing N, Devisme L, Chalabreysse L, Pasquier L, Secq V, Don M, Orsaria M, Missirian C, Mortreux J, Sanlaville D, Pons L, Küry S, Bézieau S, Liet JM, Joram N, Bihouée T, Scott DA, Brown CW, Scaglia F, Tsai AC, Grange DK, Phillips JA, Pfotenhauer JP, Jhangiani SN, Gonzaga-Jauregui CG, Chung WK, Schauer GM, Lipson MH, Mercer CL, van Haeringen A, Liu Q, Popek E, Coban Akdemir ZH, Lupski JR, Szafranski P, Isidor B, Le Caignec C & Stankiewicz P. (2019). Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway. Am. J. Hum. Genet. , , . PMID: 30639323 DOI.
  5. ↑ 5.0 5.1 Lee KY, Singh MK, Ussar S, Wetzel P, Hirshman MF, Goodyear LJ, Kispert A & Kahn CR. (2015). Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism. Nat Commun , 6, 8054. PMID: 26299309 DOI.
  6. ↑ Choe CP & Crump JG. (2014). Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a. Development , 141, 3583-93. PMID: 25142463 DOI.
  7. ↑ Funato N, Nakamura M, Richardson JA, Srivastava D & Yanagisawa H. (2012). Tbx1 regulates oral epithelial adhesion and palatal development. Hum. Mol. Genet. , 21, 2524-37. PMID: 22371266 DOI.
  8. ↑ Galli A, Robay D, Osterwalder M, Bao X, Bénazet JD, Tariq M, Paro R, Mackem S & Zeller R. (2010). Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. , 6, e1000901. PMID: 20386744 DOI.
  9. ↑ Fisher M, Downie H, Welten MC, Delgado I, Bain A, Planzer T, Sherman A, Sang H & Tickle C. (2011). Comparative analysis of 3D expression patterns of transcription factor genes and digit fate maps in the developing chick wing. PLoS ONE , 6, e18661. PMID: 21526123 DOI.
  10. ↑ Farin HF, Lüdtke TH, Schmidt MK, Placzko S, Schuster-Gossler K, Petry M, Christoffels VM & Kispert A. (2013). Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. PLoS Genet. , 9, e1003467. PMID: 23633963 DOI.
  11. ↑ Arora R, Metzger RJ & Papaioannou VE. (2012). Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS Genet. , 8, e1002866. PMID: 22876201 DOI.
  12. ↑ van den Boogaard M, Wong LY, Tessadori F, Bakker ML, Dreizehnter LK, Wakker V, Bezzina CR, 't Hoen PA, Bakkers J, Barnett P & Christoffels VM. (2012). Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. J. Clin. Invest. , 122, 2519-30. PMID: 22706305 DOI.
  13. ↑ Mc Laughlin D, Murphy P & Puri P. (2014). Altered Tbx1 gene expression is associated with abnormal oesophageal development in the adriamycin mouse model of oesophageal atresia/tracheo-oesophageal fistula. Pediatr. Surg. Int. , 30, 143-9. PMID: 24356861 DOI.
  14. ↑ Kispert A. (2017). T-Box Genes in the Kidney and Urinary Tract. Curr. Top. Dev. Biol. , 122, 245-278. PMID: 28057266 DOI.


Search Bookshelf Tbx

Reviews

Sheeba CJ & Logan MP. (2017). The Roles of T-Box Genes in Vertebrate Limb Development. Curr. Top. Dev. Biol. , 122, 355-381. PMID: 28057270 DOI.

Kispert A. (2017). T-Box Genes in the Kidney and Urinary Tract. Curr. Top. Dev. Biol. , 122, 245-278. PMID: 28057266 DOI.

Buckingham M & Relaix F. (2007). The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions. Annu. Rev. Cell Dev. Biol. , 23, 645-73. PMID: 17506689 DOI.

Mansouri A, Goudreau G & Gruss P. (1999). Pax genes and their role in organogenesis. Cancer Res. , 59, 1707s-1709s; discussion 1709s-1710s. PMID: 10197584

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Cite this page: Hill, M.A. (2023, December 2) Embryology Developmental Signals - Tbx. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Tbx

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