Transcriptional Control of Left–Right Patterning in Cardiac Development

Abstract

The heart develops from a simple left–right (L–R) symmetrical tube. Through a complex process of looping and remodelling, it becomes a highly L–R asymmetrical organ with distinct asymmetries in both morphology and function. Abnormal cardiac L–R patterning can result in a spectrum of defects that include, dextrocardia (a malposition of the heart to the right), isomerism of the atria (both atria being morphologically right-sided or left-sided), abnormal ventricular topology (e.g. the morphological left ventricle being dextral to the morphological right ventricle) or mirror-image topology (associated with situs inversus). Intermediate forms include abnormalities such as situs ambiguus and heterotaxia. L–R patterning abnormalities are typically associated with cardiac malformations, and it has become clear that an isolated septal, outflow tract and aortic arch malformation may be the only presenting manifestation of an L–R patterning defect. In the last two decades, there have been seminal advances in our understanding of the mechanisms controlling L–R patterning, and how mutations in L–R patterning genes result in human cardiac malformation. In this review, we provide an overview of the transcriptional mechanisms that result in asymmetric gene activation in mammals, how they receive information from signalling pathways, and how this translates to abnormal cardiac development.

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References

  1. 1.

    Ang SL, Rossant J (1994) HNF-3 beta is essential for node and notochord formation in mouse development. Cell 78:561–574

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J (1996) A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 122:243–252

    CAS  PubMed  Google Scholar 

  3. 3.

    Bamforth SD, Braganca J, Eloranta JJ, Murdoch JN, Marques FI, Kranc KR, Farza H, Henderson DJ, Hurst HC, Bhattacharya S (2001) Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet 29:469–474

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Bamforth SD, Braganca J, Farthing CR, Schneider JE, Broadbent C, Michell AC, Clarke K, Neubauer S, Norris D, Brown NA, Anderson RH, Bhattacharya S (2004) Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nat Genet 36:1189–1196

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N, Rossier C, Jorissen M, Armengot M, Meeks M, Mitchison HM, Chung EM, Delozier-Blanchet CD, Craigen WJ, Antonarakis SE (2002) Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci USA 99:10282–10286

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Beckers A, Alten L, Viebahn C, Andre P, Gossler A (2007) The mouse homeobox gene Noto regulates node morphogenesis, notochordal ciliogenesis, and left right patterning. Proc Natl Acad Sci USA 104:15765–15770

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Biddle FG, Jung JD, Eales BA (1991) Genetically determined variation in the azygos vein in the mouse. Teratology 44:675–683

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Blum M, Andre P, Muders K, Schweickert A, Fischer A, Bitzer E, Bogusch S, Beyer T, van Straaten HW, Viebahn C (2007) Ciliation and gene expression distinguish between node and posterior notochord in the mammalian embryo. Differentiation 75:133–146

    Article  CAS  PubMed  Google Scholar 

  9. 9.

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

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Chang H, Zwijsen A, Vogel H, Huylebroeck D, Matzuk MM (2000) Smad5 is essential for left-right asymmetry in mice. Dev Biol 219:71–78

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Cohen ED, Tian Y, Morrisey EE (2008) Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal. Development 135:789–798

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (2005) Vertebrate Smoothened functions at the primary cilium. Nature 437:1018–1021

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Franco D, Campione M (2003) The Role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends Cardiovasc Med 13:157–163

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Gaio U, Schweickert A, Fischer A, Garratt AN, Muller T, Ozcelik C, Lankes W, Strehle M, Britsch S, Blum M, Birchmeier C (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 

  15. 15.

    Hadjantonakis AK, Pisano E, Papaioannou VE (2008) Tbx6 regulates left/right patterning in mouse embryos through effects on Nodal cilia and periNodal signaling. PLoS ONE 3:e2511

    Article  PubMed  Google Scholar 

  16. 16.

    Hamada H, Meno C, Watanabe D, Saijoh Y (2002) Establishment of vertebrate left-right asymmetry. Nat Rev Genet 3:103–113

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Harvey RP (2002) Patterning the vertebrate heart. Nat Rev Genet 3:544–556

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    High FA, Epstein JA (2008) The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet 9:49–61

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Hirokawa N, Tanaka Y, Okada Y, Takeda S (2006) Nodal flow and the generation of left-right asymmetry. Cell 125:33–45

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Hiruma T, Nakajima Y, Nakamura H (2002) Development of pharyngeal arch arteries in early mouse embryo. J Anat 201:15–29

    Article  PubMed  Google Scholar 

  21. 21.

    Hong SK, Dawid IB (2009) FGF-dependent left-right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1. Proc Natl Acad Sci USA 106:2230–2235

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Hoodless PA, Pye M, Chazaud C, Labbe E, Attisano L, Rossant J, Wrana JL (2001) FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev 15:1257–1271

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Kishigami S, Yoshikawa S, Castranio T, Okazaki K, Furuta Y, Mishina Y (2004) BMP signaling through ACVRI is required for left-right patterning in the early mouse embryo. Dev Biol 276:185–193

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Krebs LT, Iwai N, Nonaka S, Welsh IC, Lan Y, Jiang R, Saijoh Y, O’Brien TP, Hamada H, Gridley T (2003) Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev 17:1207–1212

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Lee JD, Anderson KV (2008) Morphogenesis of the node and notochord: the cellular basis for the establishment and maintenance of left-right asymmetry in the mouse. Dev Dyn 237:3464–3476

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C (1995) A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82:803–814

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Liu C, Liu W, Palie J, Lu MF, Brown NA, Martin JF (2002) Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 129:5081–5091

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Macdonald ST, Bamforth SD, Chen CM, Farthing CR, Franklyn A, Broadbent C, Schneider JE, Saga Y, Lewandoski M, Bhattacharya S (2008) Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovasc Res

  29. 29.

    McGrath J, Somlo S, Makova S, Tian X, Brueckner M (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61–73

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, Ohishi S, Noji S, Kondoh H, Hamada H (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 

  31. 31.

    Meno C, Takeuchi J, Sakuma R, Koshiba-Takeuchi K, Ohishi S, Saijoh Y, Miyazaki J, ten Dijke P, Ogura T, Hamada H (2001) Diffusion of Nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev Cell 1:127–138

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Meyers EN, Martin GR (1999) Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403–406

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Mine N, Anderson RM, Klingensmith J (2008) BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment. Development 135:2425–2434

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, Yamaguchi TP (2005) Wnt3alinks left-right determination with segmentation and anteroposterior axis elongation. Development 132:5425–5436

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Neugebauer JM, Amack JD, Peterson AG, Bisgrove BW, Yost HJ (2009) FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458:651–654

    Article  CAS  PubMed  Google Scholar 

  36. 36.

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

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Norris DP, Brennan J, Bikoff EK, Robertson EJ (2002) The FoxH1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129:3455–3468

    CAS  PubMed  Google Scholar 

  38. 38.

    Nowotschin S, Liao J, Gage PJ, Epstein JA, Campione M, Morrow BE (2006) Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 133:1565–1573

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada H, Hirokawa N (1999) Abnormal Nodal flow precedes situs inversus in iv and inv mice. Mol Cell 4:459–468

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Oki S, Hashimoto R, Okui Y, Shen MM, Mekada E, Otani H, Saijoh Y, Hamada H (2007) Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo. Development 134:3893–3904

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Olbrich H, Haffner K, Kispert A, Volkel A, Volz A, Sasmaz G, Reinhardt R, Hennig S, Lehrach H, Konietzko N, Zariwala M, Noone PG, Knowles M, Mitchison HM, Meeks M, Chung EM, Hildebrandt F, Sudbrak R, Omran H (2002) Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet 30:143–144

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Przemeck GK, Heinzmann U, Beckers J, Hrabe de Angelis M (2003) Node and midline defects are associated with left-right development in Delta1 mutant embryos. Development 130:3–13

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    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 

  44. 44.

    Rana AA, Barbera JP, Rodriguez TA, Lynch D, Hirst E, Smith JC, Beddington RS (2004) Targeted deletion of the novel cytoplasmic dynein mD2LIC disrupts the embryonic organiser, formation of the body axes and specification of ventral cell fates. Development 131:4999–5007

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Rashbass P, Wilson V, Rosen B, Beddington RS (1994) Alterations in gene expression during mesoderm formation and axial patterning in Brachyury (T) embryos. Int J Dev Biol 38:35–44

    CAS  PubMed  Google Scholar 

  46. 46.

    Raya A, Kawakami Y, Rodriguez-Esteban C, Buscher D, Koth CM, Itoh T, Morita M, Raya RM, Dubova I, Bessa JG, de la Pompa JL, Belmonte JC (2003) Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos. Genes Dev 17:1213–1218

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Raya A, Kawakami Y, Rodriguez-Esteban C, Ibanes M, Rasskin-Gutman D, Rodriguez-Leon J, Buscher D, Feijo JA, Izpisua Belmonte JC (2004) Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature 427:121–128

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104:933–942

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Roessler E, Ouspenskaia MV, Karkera JD, Velez JI, Kantipong A, Lacbawan F, Bowers P, Belmont JW, Towbin JA, Goldmuntz E, Feldman B, Muenke M (2008) Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet 83:18–29

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Roy S (2009) The motile cilium in development and disease: emerging new insights. Bioessays 31:694–699

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Saijoh Y, Adachi H, Sakuma R, Yeo CY, Yashiro K, Watanabe M, Hashiguchi H, Mochida K, Ohishi S, Kawabata M, Miyazono K, Whitman M, Hamada H (2000) Left-right asymmetric expression of Lefty2 and Nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol Cell 5:35–47

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Schier AF (2003) Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol 19:589–621

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Schwabe GC, Hoffmann K, Loges NT, Birker D, Rossier C, de Santi MM, Olbrich H, Fliegauf M, Failly M, Liebers U, Collura M, Gaedicke G, Mundlos S, Wahn U, Blouin JL, Niggemann B, Omran H, Antonarakis SE, Bartoloni L (2007) Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 Mutations. Hum Mutat

  54. 54.

    Shawlot W, Behringer RR (1995) Requirement for Lim1 in head-organizer function. Nature 374:425–430

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Shiratori H, Hamada H (2006) The left-right axis in the mouse: from origin to morphology. Development 133:2095–2104

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Shiratori H, Sakuma R, Watanabe M, Hashiguchi H, Mochida K, Sakai Y, Nishino J, Saijoh Y, Whitman M, Hamada H (2001) Two-step regulation of left-right asymmetric expression of Pitx2: initiation by Nodal signaling and maintenance by Nkx2. Mol Cell 7:137–149

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Slough J, Cooney L, Brueckner M (2008) Monocilia in the embryonic mouse heart suggest a direct role for cilia in cardiac morphogenesis. Dev Dyn 237:2304–2314

    Article  PubMed  Google Scholar 

  58. 58.

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

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Tabin CJ, Vogan KJ (2003) A two-cilia model for vertebrate left-right axis specification. Genes Dev 17:1–6

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Takeuchi JK, Lickert H, Bisgrove BW, Sun X, Yamamoto M, Chawengsaksophak K, Hamada H, Yost HJ, Rossant J, Bruneau BG (2007) Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry. Proc Natl Acad Sci USA 104:846–851

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Tanaka Y, Okada Y, Hirokawa N (2005) FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward Nodal flow is critical for left-right determination. Nature 435:172–177

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Tanaka C, Sakuma R, Nakamura T, Hamada H, Saijoh Y (2007) Long-range action of Nodal requires interaction with GDF1. Genes Dev 21:3272–3282

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Tessari A, Pietrobon M, Notte A, Cifelli G, Gage PJ, Schneider MD, Lembo G, Campione M (2008) Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs. Circ Res 102:813–822

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    Tsukui T, Capdevila J, Tamura K, Ruiz-Lozano P, Rodriguez-Esteban C, Yonei-Tamura S, Magallon J, Chandraratna RA, Chien K, Blumberg B, Evans RM, Belmonte JC (1999) Multiple left-right asymmetry defects in Shh(−/−) mutant mice unveil a convergence of the Shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci USA 96:11376–11381

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    van Wijk B, Moorman AF, van den Hoff MJ (2007) Role of bone morphogenetic proteins in cardiac differentiation. Cardiovasc Res 74:244–255

    Article  PubMed  Google Scholar 

  66. 66.

    Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22:2454–2472

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW (2004) Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 74:93–105

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Weninger WJ, Mohun T (2002) Phenotyping transgenic embryos: a rapid 3-D screening method based on episcopic fluorescence image capturing. Nat Genet 30:59–65

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Weninger WJ, Floro KL, Bennett MB, Withington SL, Preis JI, Barbera JP, Mohun TJ, Dunwoodie SL (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 

  70. 70.

    Yamamoto M, Meno C, Sakai Y, Shiratori H, Mochida K, Ikawa Y, Saijoh Y, Hamada H (2001) The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev 15:1242–1256

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, Meno C, Hamada H (2003) Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130:1795–1804

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    Yamanaka Y, Tamplin OJ, Beckers A, Gossler A, Rossant J (2007) Live imaging and genetic analysis of mouse notochord formation reveals regional morphogenetic mechanisms. Dev Cell 13:884–896

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Yan YT, Gritsman K, Ding J, Burdine RD, Corrales JD, Price SM, Talbot WS, Schier AF, Shen MM (1999) Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev 13:2527–2537

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Yashiro K, Shiratori H, Hamada H (2007) Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 450:285–288

    Article  CAS  PubMed  Google Scholar 

  75. 75.

    Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J, Yuan S, Prabhakar NR, Herrup K, Conlon RA, Hoit BD, Watanabe M, Yang YC (2002) The essential role of Cited2, a negative regulator for HIF-1{alpha}, in heart development and neurulation. Proc Natl Acad Sci USA 99:10488–10493

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106:781–792

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Shoumo Bhattacharya.

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Chen, C., Norris, D. & Bhattacharya, S. Transcriptional Control of Left–Right Patterning in Cardiac Development. Pediatr Cardiol 31, 371–377 (2010). https://doi.org/10.1007/s00246-009-9610-3

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Keywords

  • Left–right patterning
  • Transcription
  • Heart development