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Molecular Pathways and Animal Models of d-Transposition of the Great Arteries

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Congenital Heart Diseases: The Broken Heart

Abstract

During normal cardiovascular development, the outflow tract becomes septated and rotates so that the separate aorta and pulmonary trunk are correctly aligned with the left and right ventricles, respectively. However, when this process goes wrong, the aorta and pulmonary trunk are incorrectly positioned resulting in oxygenated blood being directly returned to the lungs, with deoxygenated blood being delivered to the systemic circulation. This is termed transposition of the great arteries (TGA). The precise etiology of TGA is not known, but the use of animal models has elucidated that genes involved in left–right determination of the embryonic body play key roles. Other factors such as retinoic acid levels are also crucial. This chapter reviews the animal models that can be manipulated genetically or with exogenous agents to present with TGA.

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References

  1. Bamforth SD, Schneider JE, Bhattacharya S (2012) High-throughput analysis of mouse embryos by magnetic resonance imaging. Cold Spring Harb Protoc 2012:93–101

    Article  PubMed  Google Scholar 

  2. Unolt M, Putotto C, Silvestri LM et al (2013) Transposition of great arteries: new insights into the pathogenesis. Front Pediatr 1:1–11

    Article  Google Scholar 

  3. Szumska D, Pieles G, Essalmani R et al (2008) VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev 22:1465–1477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Ramsdell AF (2005) Left-right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left-right axis determination. Dev Biol 288:1–20

    Article  CAS  PubMed  Google Scholar 

  5. Shiratori H, Hamada H (2014) TGF beta signaling in establishing left-right asymmetry. Semin Cell Dev Biol 32:80–84

    Article  CAS  PubMed  Google Scholar 

  6. Icardo JM, Sanchez de Vega MJ (1991) Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation 84:2547–2558

    Article  CAS  PubMed  Google Scholar 

  7. Supp DM, Witte DP, Potter SS et al (1997) Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 389:963–966

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Nonaka S, Shiratori H, Saijoh Y et al (2002) Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96–99

    Article  CAS  PubMed  Google Scholar 

  9. Okada Y, Nonaka S, Tanaka Y et al (1999) Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 4:459–468

    Article  CAS  PubMed  Google Scholar 

  10. Axelrod JD (2009) Progress and challenges in understanding planar cell polarity signaling. Semin Cell Dev Biol 20:964–971

    Article  CAS  PubMed  Google Scholar 

  11. Antic D, Stubbs JL, Suyama K et al (2010) Planar cell polarity enables posterior localization of nodal cilia and left-right axis determination during mouse and Xenopus embryogenesis. PLoS One 5, e8999

    Article  PubMed Central  PubMed  Google Scholar 

  12. Hamblet NS, Lijam N, Ruiz-Lozano P et al (2002) Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129:5827–5838

    Article  CAS  PubMed  Google Scholar 

  13. Phillips HM, Rhee HJ, Murdoch JN et al (2007) Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization. Circ Res 101:137–145

    Article  CAS  PubMed  Google Scholar 

  14. Brennan J, Norris DP, Robertson EJ (2002) Nodal activity in the node governs left-right asymmetry. Genes Dev 16:2339–2344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hyatt BA, Lohr JL, Yost HJ (1996) Initiation of vertebrate left-right axis formation by maternal Vg1. Nature 384:62–65

    Article  CAS  PubMed  Google Scholar 

  16. Wall NA, Craig EJ, Labosky PA et al (2000) Mesendoderm induction and reversal of left-right pattern by mouse Gdf1, a Vg1-related gene. Dev Biol 227:495–509

    Article  CAS  PubMed  Google Scholar 

  17. Rankin CT, Bunton T, Lawler AM et al (2000) Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat Genet 24:262–265

    Article  CAS  PubMed  Google Scholar 

  18. Karkera JD, Lee JS, Roessler E et al (2007) Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum Genet 81:987–994

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105:781–792

    Article  CAS  PubMed  Google Scholar 

  20. Botilde Y, Yoshiba S, Shinohara K et al (2013) Cluap1 localizes preferentially to the base and tip of cilia and is required for ciliogenesis in the mouse embryo. Dev Biol 381:203–212

    Article  CAS  PubMed  Google Scholar 

  21. Lin L, Bu L, Cai CL et al (2006) Isl1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis. Dev Biol 295:756–763

    Article  CAS  PubMed  Google Scholar 

  22. Oh SP, Li E (1997) The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11:1812–1826

    Article  CAS  PubMed  Google Scholar 

  23. Gaio U, Schweickert A, Fischer A et al (1999) A role of the cryptic gene in the correct establishment of the left-right axis. Curr Biol 9:1339–1342

    Article  CAS  PubMed  Google Scholar 

  24. Yan YT, Gritsman K, Ding J et al (1999) Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev 13:2527–2537

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nomura M, Li E (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393:786–790

    Article  CAS  PubMed  Google Scholar 

  26. Meno C, Shimono A, Saijoh Y et al (1998) Lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94:287–297

    Article  CAS  PubMed  Google Scholar 

  27. Meno C, Takeuchi J, Sakuma R et al (2001) Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev Cell 1:127–138

    Article  CAS  PubMed  Google Scholar 

  28. Schweickert A, Campione M, Steinbeisser H et al (2000) Pitx2 isoforms: involvement of Pitx2c but not Pitx2a or Pitx2b in vertebrate left-right asymmetry. Mech Dev 90:41–51

    Article  CAS  PubMed  Google Scholar 

  29. Kitamura K, Miura H, Miyagawa-Tomita S et al (1999) Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 126:5749–5758

    CAS  PubMed  Google Scholar 

  30. Cox CJ, Espinoza HM, McWilliams B et al (2002) Differential regulation of gene expression by PITX2 isoforms. J Biol Chem 277:25001–25010

    Article  CAS  PubMed  Google Scholar 

  31. Shiratori H, Yashiro K, Shen MM et al (2006) Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development 133:3015–3025

    Article  CAS  PubMed  Google Scholar 

  32. Bajolle F, Zaffran S, Kelly RG et al (2006) Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries. Circ Res 98:421–428

    Article  CAS  PubMed  Google Scholar 

  33. Bamforth SD, Braganca J, Farthing CR et al (2004) Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nat Genet 36:1189–1196

    Article  CAS  PubMed  Google Scholar 

  34. Weninger WJ, Floro KL, Bennett MB et al (2005) Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development. Development 132:1337–1348

    Article  CAS  PubMed  Google Scholar 

  35. Purandare SM, Ware SM, Kwan KM et al (2002) A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129:2293–2302

    CAS  PubMed  Google Scholar 

  36. D’Alessandro LC, Latney BC, Paluru PC et al (2013) The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle. Am J Med Genet A 161A:792–802

    Article  PubMed  Google Scholar 

  37. Costell M, Carmona R, Gustafsson E et al (2002) Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ Res 91:158–164

    Article  CAS  PubMed  Google Scholar 

  38. Vincent SD, Mayeuf-Louchart A, Watanabe Y et al (2014) Prdm1 functions in the mesoderm of the second heart field, where it interacts genetically with Tbx1, during outflow tract morphogenesis in the mouse embryo. Hum Mol Genet 23:5087–5101

    Article  PubMed  Google Scholar 

  39. Clouthier DE, Hosoda K, Richardson JA et al (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125:813–824

    CAS  PubMed  Google Scholar 

  40. Abu-Issa R, Smyth G, Smoak I et al (2002) Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129:4613–4625

    CAS  PubMed  Google Scholar 

  41. Park EJ, Ogden LA, Talbot A et al (2006) Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development 133:2419–2433

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Hutson MR, Zhang P, Stadt HA et al (2006) Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx. Dev Biol 295:486–497

    Article  CAS  PubMed  Google Scholar 

  43. Yasui H, Nakazawa M, Morishima M et al (1995) Morphological observations on the pathogenetic process of transposition of the great arteries induced by retinoic acid in mice. Circulation 91:2478–2486

    Article  CAS  PubMed  Google Scholar 

  44. Cipollone D, Amati F, Carsetti R et al (2006) A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice. Cardiovasc Pathol 15:194–202

    Article  CAS  PubMed  Google Scholar 

  45. Cipollone D, Carsetti R, Tagliani A et al (2009) Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice. Cardiovasc Pathol 18:100–109

    Article  CAS  PubMed  Google Scholar 

  46. Amati F, Diano L, Campagnolo L et al (2010) Hif1alpha down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist. BMC Genomics 11:497

    Article  PubMed Central  PubMed  Google Scholar 

  47. Zhu H, Wlodarczyk BJ, Scott M et al (2007) Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. Birth Defects Res A Clin Mol Teratol 79:257–268

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Professor Robert Anderson for critically reading the manuscript. SDB is the recipient of a British Heart Foundation Intermediate Basic Science Research Fellowship. A-LJ was funded by a British Heart Foundation PhD Studentship.

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Authors and Affiliations

  1. Institute of Genetic Medicine, Newcastle University, Newcastle, UK

    Amy-Leigh Johnson & Simon D. Bamforth

Authors
  1. Amy-Leigh Johnson
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  2. Simon D. Bamforth
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Corresponding author

Correspondence to Simon D. Bamforth .

Editor information

Editors and Affiliations

  1. Cardiovascular Genetics, Charité - Universitätsmedizin Berlin , Berlin, Germany

    Silke Rickert-Sperling

  2. Developmental Biology, Inst. of Marseilles, Aix-Marseille Univ. , Marseille, France

    Robert G. Kelly

  3. Dpt. of Pediatrics Div.of Pediatric Card, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    David J. Driscoll

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Johnson, AL., Bamforth, S.D. (2016). Molecular Pathways and Animal Models of d-Transposition of the Great Arteries. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_36

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