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Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome

  • Immune Deficiency and Dysregulation (DP Huston, Section Editor)
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Abstract

22q11.2 deletion syndrome (22q11.2DS) is caused by a commonly occurring microdeletion on chromosome 22. Clinical findings include cardiac malformations, thymic and parathyroid hypoplasia, craniofacial dysmorphisms, and dental defects. These phenotypes are due mainly to abnormal development of the pharyngeal apparatus. Targeted deletion studies in mice and analysis of naturally occurring mutations in humans have implicated Tbx1 as a candidate gene for 22q11.2DS. Tbx1 belongs to an evolutionarily conserved T-box family of transcription factors, whose expression is precisely regulated during embryogenesis, and it appears to regulate the proliferation and differentiation of various progenitor cells during organogenesis. In this review, we discuss the mechanisms of Tbx1 during development of the heart, thymus and parathyroid glands, as well as during formation of the palate, teeth, and other craniofacial features.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Devriendt K, Fryns JP, Mortier G, et al. The annual incidence of DiGeorge/velocardiofacial syndrome. J Med Genet. 1998;35:789–90.

    Article  PubMed  CAS  Google Scholar 

  2. Goldberg R, Motzkin B, Marion R, et al. Velo-cardio-facial syndrome: a review of 120 patients. Am J Med Genet. 1993;45:313–9.

    Article  PubMed  CAS  Google Scholar 

  3. Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. 1978;15:56–62.

    PubMed  CAS  Google Scholar 

  4. Klingberg G, Oskarsdottir S, Johannesson EL, et al. Oral manifestations in 22q11 deletion syndrome. Int J Paediatr Dent. 2002;12:14–23.

    PubMed  CAS  Google Scholar 

  5. Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet. 2000;9:489–501.

    Article  PubMed  CAS  Google Scholar 

  6. Baumer A, Riegel M, Schinzel A. Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion. J Med Genet. 2004;41:413–20.

    Article  PubMed  CAS  Google Scholar 

  7. Lindsay EA, Botta A, Jurecic V, et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature. 1999;401:379–83.

    PubMed  CAS  Google Scholar 

  8. Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410:97–101.

    Article  PubMed  CAS  Google Scholar 

  9. Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27:286–91.

    Article  PubMed  CAS  Google Scholar 

  10. Merscher S, Funke B, Epstein JA, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell. 2001;104:619–29.

    Article  PubMed  CAS  Google Scholar 

  11. Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366–73.

    Article  PubMed  CAS  Google Scholar 

  12. Bollag RJ, Siegfried Z, Cebra-Thomas JA, et al. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Nat Genet. 1994;7:383–9.

    Article  PubMed  CAS  Google Scholar 

  13. Xu H, Cerrato F, Baldini A. Timed mutation and cell-fate mapping reveal reiterated roles of Tbx1 during embryogenesis, and a crucial function during segmentation of the pharyngeal system via regulation of endoderm expansion. Development. 2005;132:4387–95.

    Article  PubMed  CAS  Google Scholar 

  14. Chapman DL, Garvey N, Hancock S, et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev Dyn. 1996;206:379–90.

    Article  PubMed  CAS  Google Scholar 

  15. Vitelli F, Morishima M, Taddei I, et al. Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum Mol Genet. 2002;11:915–22.

    Article  PubMed  CAS  Google Scholar 

  16. Yamagishi H, Maeda J, Hu T, et al. Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer. Genes Dev. 2003;17:269–81.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang Z, Baldini A. In vivo response to high-resolution variation of Tbx1 mRNA dosage. Hum Mol Genet. 2008;17:150–7.

    Article  PubMed  CAS  Google Scholar 

  18. Vitelli F, Huynh T, Baldini A. Gain of function of Tbx1 affects pharyngeal and heart development in the mouse. Genesis. 2009;47:188–95.

    Article  PubMed  CAS  Google Scholar 

  19. Liao J, Kochilas L, Nowotschin S, et al. Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage. Hum Mol Genet. 2004;13:1577–85.

    Article  PubMed  CAS  Google Scholar 

  20. McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Med (Baltimore). 2011;90:1–18.

    Article  Google Scholar 

  21. Zhang Z, Cerrato F, Xu H, et al. Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development. Development. 2005;132:5307–15.

    Article  PubMed  CAS  Google Scholar 

  22. Yutzey KE. DiGeorge syndrome, Tbx1, and retinoic acid signaling come full circle. Circ Res. 2010;106:630–2.

    Article  PubMed  CAS  Google Scholar 

  23. Roberts C, Ivins SM, James CT, et al. Retinoic acid down-regulates Tbx1 expression in vivo and in vitro. Dev Dyn. 2005;232:928–38.

    Article  PubMed  CAS  Google Scholar 

  24. Vermot J, Niederreither K, Garnier JM, et al. Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proc Natl Acad Sci U S A. 2003;100:1763–8.

    Article  PubMed  CAS  Google Scholar 

  25. Ryckebusch L, Bertrand N, Mesbah K, et al. Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circ Res. 2010;106:686–94.

    Article  PubMed  Google Scholar 

  26. Roberts C, Ivins S, Cook AC, et al. Cyp26 genes a1, b1 and c1 are down-regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge Syndrome in the chick. Hum Mol Genet. 2006;15:3394–410.

    Article  PubMed  CAS  Google Scholar 

  27. Guris DL, Fantes J, Tara D, et al. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet. 2001;27:293–8.

    Article  PubMed  CAS  Google Scholar 

  28. Guris DL, Duester G, Papaioannou VE, et al. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell. 2006;10:81–92.

    Article  PubMed  CAS  Google Scholar 

  29. • Voss AK, Vanyai HK, Collin C, et al. MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome. Dev Cell. 2012;23:652–63. This article showed that a chromatin modifier, MOZ, is a critical regulator of Tbx1 in vivo.

    Article  PubMed  CAS  Google Scholar 

  30. Randall V, McCue K, Roberts C, et al. Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice. J Clin Invest. 2009;119:3301–10.

    PubMed  CAS  Google Scholar 

  31. Hutson MR, Kirby ML. Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations. Semin Cell Dev Biol. 2007;18:101–10.

    Article  PubMed  CAS  Google Scholar 

  32. Calmont A, Ivins S, Van Bueren KL, et al. Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm. Development. 2009;136:3173–83.

    Article  PubMed  CAS  Google Scholar 

  33. Byrd NA, Meyers EN. Loss of Gbx2 results in neural crest cell patterning and pharyngeal arch artery defects in the mouse embryo. Dev Biol. 2005;284:233–45.

    Article  PubMed  CAS  Google Scholar 

  34. Papangeli I, Scambler PJ. Tbx1 genetically interacts with the transforming growth factor-beta/bone morphogenetic protein inhibitor Smad7 during great vessel remodeling. Circ Res. 2013;112:90–102.

    Article  PubMed  CAS  Google Scholar 

  35. Xu H, Morishima M, Wylie JN, et al. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development. 2004;131:3217–27.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang Z, Huynh T, Baldini A. Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development. 2006;133:3587–95.

    Article  PubMed  CAS  Google Scholar 

  37. Kelly RG. The second heart field. Curr Top Dev Biol. 2012;100:33–65.

    Article  PubMed  CAS  Google Scholar 

  38. Huynh T, Chen L, Terrell P, et al. A fate map of Tbx1 expressing cells reveals heterogeneity in the second cardiac field. Genesis. 2007;45:470–5.

    Article  PubMed  CAS  Google Scholar 

  39. Liao J, Aggarwal VS, Nowotschin S, et al. Identification of downstream genetic pathways of Tbx1 in the second heart field. Dev Biol. 2008;316:524–37.

    Article  PubMed  CAS  Google Scholar 

  40. Chen L, Fulcoli FG, Tang S, et al. Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circ Res. 2009;105:842–51.

    Article  PubMed  CAS  Google Scholar 

  41. Tirosh-Finkel L, Zeisel A, Brodt-Ivenshitz M, et al. BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. Development. 2010;137:2989–3000.

    Article  PubMed  CAS  Google Scholar 

  42. Dyer LA, Kirby ML. Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation. Dev Biol. 2009;330:305–17.

    Article  PubMed  CAS  Google Scholar 

  43. Garg V, Yamagishi C, Hu T, et al. Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev Biol. 2001;235:62–73.

    Article  PubMed  CAS  Google Scholar 

  44. Hu T, Yamagishi H, Maeda J, et al. Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Development. 2004;131:5491–502.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang Z, Baldini A. Manipulation of endogenous regulatory elements and transgenic analyses of the Tbx1 gene. Mamm Genome. 2010;21:556–64.

    Article  PubMed  CAS  Google Scholar 

  46. Park EJ, Ogden LA, Talbot A, et al. Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development. 2006;133:2419–33.

    Article  PubMed  CAS  Google Scholar 

  47. Watanabe Y, Zaffran S, Kuroiwa A, et al. Fibroblast growth factor 10 gene regulation in the second heart field by Tbx, 1, Nkx2–5, and Islet1 reveals a genetic switch for down-regulation in the myocardium. Proc Natl Acad Sci U S A. 2012;109:18273–80.

    Article  PubMed  CAS  Google Scholar 

  48. Vitelli F, Taddei I, Morishima M, et al. A genetic link between Tbx1 and fibroblast growth factor signaling. Development. 2002;129:4605–11.

    PubMed  CAS  Google Scholar 

  49. Moon AM, Guris DL, Seo JH, et al. Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell. 2006;10:71–80.

    Article  PubMed  CAS  Google Scholar 

  50. • Wang J, Greene SB, Bonilla-Claudio M, et al. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Dev Cell. 2010;19:903–12. This article is the first to indicate that Bmp signaling is involved in a BmpmicroRNA-17-92 regulatory pathway in order to down-regulate cardiac progentior genes and to enhance myocardial differentiation.

    Article  PubMed  CAS  Google Scholar 

  51. Prall OW, Menon MK, Solloway MJ, et al. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell. 2007;128:947–59.

    Article  PubMed  CAS  Google Scholar 

  52. Fulcoli FG, Huynh T, Scambler PJ, et al. Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner. PLoS One. 2009;4:e6049.

    Article  PubMed  Google Scholar 

  53. Pane LS, Zhang Z, Ferrentino R, et al. Tbx1 is a negative modulator of Mef2c. Hum Mol Genet. 2012;21:2485–96.

    Article  PubMed  CAS  Google Scholar 

  54. Liu C, Liu W, Palie J, et al. Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development. 2002;129:5081–91.

    Article  PubMed  CAS  Google Scholar 

  55. Nowotschin S, Liao J, Gage PJ, et al. Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development. 2006;133:1565–73.

    Article  PubMed  CAS  Google Scholar 

  56. Chen L, Fulcoli FG, Ferrentino R, et al. Transcriptional control in cardiac progenitors: Tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a. PLoS Genet. 2012;8:e1002571.

    Article  PubMed  CAS  Google Scholar 

  57. Person AD, Beiraghi S, Sieben CM, et al. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239:327–37.

    PubMed  CAS  Google Scholar 

  58. Gordon J, Wilson VA, Blair NF, et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol. 2004;5:546–53.

    Article  PubMed  CAS  Google Scholar 

  59. Zou D, Silvius D, Davenport J, et al. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev Biol. 2006;293:499–512.

    Article  PubMed  CAS  Google Scholar 

  60. Guo C, Sun Y, Zhou B, et al. A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J Clin Invest. 2011;121:1585–95.

    Article  PubMed  CAS  Google Scholar 

  61. Marom T, Roth Y, Goldfarb A, et al. Head and neck manifestations of 22q11.2 deletion syndromes. Eur Arch Otorhinolaryngol. 2012;269:381–7.

    Article  PubMed  Google Scholar 

  62. Zoupa M, Seppala M, Mitsiadis T, et al. Tbx1 is expressed at multiple sites of epithelial-mesenchymal interaction during early development of the facial complex. Int J Dev Biol. 2006;50:504–10.

    Article  PubMed  Google Scholar 

  63. • Funato N, Nakamura M, Richardson JA, et al. Tbx1 regulates oral epithelial adhesion and palatal development. Hum Mol Genet. 2012;21:2524–37. First study to examine epithelial adhesion during palatal development by conditionally knocking out Tbx1 specifically in the keratinocyte lineage.

    Article  PubMed  CAS  Google Scholar 

  64. Goudy S, Law A, Sanchez G, et al. Tbx1 is necessary for palatal elongation and elevation. Mech Dev. 2010;127:292–300.

    Article  PubMed  CAS  Google Scholar 

  65. Okano J, Kimura W, Papaionnou VE, et al. The regulation of endogenous retinoic acid level through CYP26B1 is required for elevation of palatal shelves. Dev Dyn. 2012;241:1744–56.

    Article  PubMed  CAS  Google Scholar 

  66. Nordgarden H, Lima K, Skogedal N, et al. Dental developmental disturbances in 50 individuals with the 22q11.2 deletion syndrome; relation to medical conditions? Acta Odontol Scand. 2012;70:194–201.

    Article  PubMed  CAS  Google Scholar 

  67. Thesleff I. The genetic basis of tooth development and dental defects. Am J Med Genet A. 2006;140:2530–5.

    Article  PubMed  Google Scholar 

  68. Mitsiadis TA, Tucker AS, De Bari C, et al. A regulatory relationship between Tbx1 and FGF signaling during tooth morphogenesis and ameloblast lineage determination. Dev Biol. 2008;320:39–48.

    Article  PubMed  CAS  Google Scholar 

  69. • Cao H, Florez S, Amen M, et al. Tbx1 regulates progenitor cell proliferation in the dental epithelium by modulating Pitx2 activation of p21. Dev Biol. 2010;347:289–300. Important study that examines the role of Tbx1 during incisor and molar development in mice. A new molecular mechanism between Tbx1, Pitx2, and p21 is also identified.

    Article  PubMed  CAS  Google Scholar 

  70. Caton J, Luder HU, Zoupa M, et al. Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors. Dev Biol. 2009;328:493–505.

    Article  PubMed  CAS  Google Scholar 

  71. Hjalt TA, Semina EV, Amendt BA, et al. The Pitx2 protein in mouse development. Dev Dyn. 2000;218:195–200.

    Article  PubMed  CAS  Google Scholar 

  72. Harada H, Toyono T, Toyoshima K, et al. FGF10 maintains stem cell compartment in developing mouse incisors. Development. 2002;129:1533–41.

    PubMed  CAS  Google Scholar 

  73. • Chen T, Heller E, Beronja S, et al. An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration. Nature. 2012;485:104–8. TBX1 is discovered to be a regulator for the transition between quiescent follicular stem cells and proliferative hair follicles.

    Article  PubMed  CAS  Google Scholar 

  74. Zhang L, Yuan G, Liu H, et al. Expression pattern of Sox2 during mouse tooth development. Gene Expr Patterns. 2012;12:273–81.

    Article  PubMed  CAS  Google Scholar 

  75. • Juuri E, Saito K, Ahtiainen L, et al. Sox2+ stem cells contribute to all epithelial lineages of the tooth via Sfrp5+ progenitors. Dev Cell. 2012;23:317–28. First paper to identify an epithelial stem cell marker for the mouse incisor.

    Article  PubMed  CAS  Google Scholar 

  76. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.

    Article  PubMed  CAS  Google Scholar 

  77. Michon F, Tummers M, Kyyronen M, et al. Tooth morphogenesis and ameloblast differentiation are regulated by micro-RNAs. Dev Biol. 2010;340:355–68.

    Article  PubMed  CAS  Google Scholar 

  78. • Cao H, Wang J, Li X, et al. MicroRNAs play a critical role in tooth development. J Dent Res. 2010;89:779–84. An important article showing that microRNAs play a critical role in the development of incisors and molars in the mouse tooth.

    Article  PubMed  CAS  Google Scholar 

  79. Jheon AH, Li CY, Wen T, et al. Expression of microRNAs in the stem cell niche of the adult mouse incisor. PLoS One. 2011;6:e24536.

    Article  PubMed  CAS  Google Scholar 

  80. Bachiller D, Klingensmith J, Shneyder N, et al. The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development. 2003;130:3567–78.

    Article  PubMed  CAS  Google Scholar 

  81. Choi M, Klingensmith J. Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse. PLoS Genet. 2009;5:e1000395.

    Article  PubMed  Google Scholar 

  82. Harel I, Maezawa Y, Avraham R, et al. Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis. Proc Natl Acad Sci U S A. 2012;109:18839–44.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Support for this work was provided from grants DE013941 and DE018885 from the National Institute of Dental and Craniofacial Research. We thank members of the Amendt laboratory for helpful discussions and Christine Blaumueller for editorial expertise.

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Shan Gao, Xiao Li, and Brad A. Amendt declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human subjects performed by any of the authors. With regard to the author’s research cited in this paper, all institutional and national guidelines for the care and use of laboratory animals were followed.

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Gao, S., Li, X. & Amendt, B.A. Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome. Curr Allergy Asthma Rep 13, 613–621 (2013). https://doi.org/10.1007/s11882-013-0384-6

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