Abstract
Tetralogy of Fallot and double outlet right ventricle are outflow tract (OFT) alignment defects situated on a continuous disease spectrum. A myriad of upstream causes can impact on ventriculoarterial alignment that can be summarized as defects in either (1) OFT elongation during looping morphogenesis or (2) OFT remodeling during cardiac septation. Embryological processes underlying these two developmental steps include deployment of second heart field cardiac progenitor cells, establishment and transmission of embryonic left/right information driving OFT rotation, and OFT cushion and valve morphogenesis. The formation and remodeling of pulmonary trunk infundibular myocardium are critical components of both steps. Importantly, OFT alignment is mechanistically distinct from neural crest-driven OFT septation, although neural crest cells impact indirectly on alignment through their role in modulating signaling during SHF development. As yet poorly understood non-genetic causes of alignment defects that impact the above processes include hemodynamic changes, the uterine environment, and stochastic events. The heterogeneity of causes converging on alignment defects characterizes the OFT as a hotspot of congenital heart defects.
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References
Kelly RG (2012) The second heart field. Curr Top Dev Biol 100:33–65
Dyer LA, Kirby ML (2009) The role of secondary heart field in cardiac development. Dev Biol 336:137–144
Miquerol L, Kelly RG (2013) Organogenesis of the vertebrate heart. Wiley Interdiscip Rev Dev Biol 2:17–29
Hutson MR, Kirby ML (2003) Neural crest and cardiovascular development: a 20-year perspective. Birth Defects Res C Embryo Today 69:2–13
Yelbuz TM, Waldo KL, Kumiski DH et al (2002) Shortened outflow tract leads to altered cardiac looping after neural crest ablation. Circulation 106:504–510
Di Felice V, Zummo G (2009) Tetralogy of fallot as a model to study cardiac progenitor cell migration and differentiation during heart development. Trends Cardiovasc Med 19:130–135
Van Praagh R (2009) The first Stella van Praagh memorial lecture: the history and anatomy of tetralogy of Fallot. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu: 19–38
Ward C, Stadt H, Hutson M et al (2005) Ablation of the secondary heart field leads to tetralogy of Fallot and pulmonary atresia. Dev Biol 284:72–83
Parisot P, Mesbah K, Theveniau-Ruissy M et al (2011) Tbx1, subpulmonary myocardium and conotruncal congenital heart defects. Birth Defects Res A Clin Mol Teratol 91:477–484
Rana MS, Theveniau-Ruissy M, De Bono C et al (2014) Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart. Circ Res 115:790–799
Bertrand N, Roux M, Ryckebusch L et al (2011) Hox genes define distinct progenitor sub-domains within the second heart field. Dev Biol 353:266–274
Dominguez JN, Meilhac SM, Bland YS et al (2012) Asymmetric fate of the posterior part of the second heart field results in unexpected left/right contributions to both poles of the heart. Circ Res 111:1323–1335
Lescroart F, Mohun T, Meilhac SM et al (2012) Lineage tree for the venous pole of the heart: clonal analysis clarifies controversial genealogy based on genetic tracing. Circ Res 111:1313–1322
Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104:933–942
Theveniau-Ruissy M, Dandonneau M, Mesbah K et al (2008) The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning. Circ Res 103:142–148
Baldini A (2005) Dissecting contiguous gene defects: TBX1. Curr Opin Genet Dev 15:279–284
Chen L, Fulcoli FG, Tang S et al (2009) Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circ Res 105:842–851
Liao J, Aggarwal VS, Nowotschin S et al (2008) Identification of downstream genetic pathways of Tbx1 in the second heart field. Dev Biol 316:524–537
Zhang Z, Baldini A (2008) In vivo response to high-resolution variation of Tbx1 mRNA dosage. Hum Mol Genet 17:150–157
Prall OW, Menon MK, Solloway MJ et al (2007) An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128:947–959
Laforest B, Nemer M (2011) GATA5 interacts with GATA4 and GATA6 in outflow tract development. Dev Biol 358:368–378
Raid R, Krinka D, Bakhoff L et al (2009) Lack of Gata3 results in conotruncal heart anomalies in mouse. Mech Dev 126:80–89
Tevosian SG, Deconinck AE, Tanaka M et al (2000) FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101:729–739
Crispino JD, Lodish MB, Thurberg BL et al (2001) Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev 15:839–844
Makki N, Capecchi MR (2012) Cardiovascular defects in a mouse model of HOXA1 syndrome. Hum Mol Genet 21:26–31
Ilagan R, Abu-Issa R, Brown D et al (2006) Fgf8 is required for anterior heart field development. Development 133:2435–2445
Marguerie A, Bajolle F, Zaffran S et al (2006) Congenital heart defects in Fgfr2-IIIb and Fgf10 mutant mice. Cardiovasc Res 71:50–60
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
Park EJ, Watanabe Y, Smyth G et al (2008) An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Development 135:3599–3610
Watanabe Y, Miyagawa-Tomita S, Vincent SD et al (2010) Role of mesodermal FGF8 and FGF10 overlaps in the development of the arterial pole of the heart and pharyngeal arch arteries. Circ Res 106:495–503
Vincentz JW, McWhirter JR, Murre C et al (2005) Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis 41:192–201
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
Donovan J, Kordylewska A, Jan YN et al (2002) Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice. Curr Biol 12:1605–1610
Rochais F, Dandonneau M, Mesbah K et al (2009) Hes1 is expressed in the second heart field and is required for outflow tract development. PLoS One 4:e6267
High FA, Jain R, Stoller JZ et al (2009) Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. J Clin Invest 119:1986–1996
McCright B, Lozier J, Gridley T (2002) A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129:1075–1082
High FA, Lu MM, Pear WS et al (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A 105:1955–1959
Nakajima M, Moriizumi E, Koseki H et al (2004) Presenilin 1 is essential for cardiac morphogenesis. Dev Dyn 230:795–799
Cohen ED, Wang Z, Lepore JJ et al (2007) Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. J Clin Invest 117:1794–1804
Dyer LA, Kirby ML (2009) Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation. Dev Biol 330:305–317
Hoffmann AD, Peterson MA, Friedland-Little JM et al (2009) sonic hedgehog is required in pulmonary endoderm for atrial septation. Development 136:1761–1770
Washington Smoak I, Byrd NA et al (2005) Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev Biol 283:357–372
Li P, Pashmforoush M, Sucov HM (2010) Retinoic acid regulates differentiation of the secondary heart field and TGFbeta-mediated outflow tract septation. Dev Cell 18:480–485
Yasui H, Morishima M, Nakazawa M et al (1999) Developmental spectrum of cardiac outflow tract anomalies encompassing transposition of the great arteries and dextroposition of the aorta: pathogenic effect of extrinsic retinoic acid in the mouse embryo. Anat Rec 254:253–260
Ratajska A, Zlotorowicz R, Blazejczyk M et al (2005) Coronary artery embryogenesis in cardiac defects induced by retinoic acid in mice. Birth Defects Res A Clin Mol Teratol 73:966–979
Henderson DJ, Phillips HM, Chaudhry B (2006) Vang-like 2 and noncanonical Wnt signaling in outflow tract development. Trends Cardiovasc Med 16:38–45
Sinha T, Wang B, Evans S et al (2012) Disheveled mediated planar cell polarity signaling is required in the second heart field lineage for outflow tract morphogenesis. Dev Biol 370:135–144
Ramsbottom SA, Sharma V, Rhee HJ et al (2014) Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development. PLoS Genet 10:e1004871
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
Schleiffarth JR, Person AD, Martinsen BJ et al (2007) Wnt5a is required for cardiac outflow tract septation in mice. Pediatr Res 61:386–391
Zhou W, Lin L, Majumdar A, Li X et al (2007) Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nat Genet 39:1225–1234
Cohen ED, Miller MF, Wang Z et al (2012) Wnt5a and Wnt11 are essential for second heart field progenitor development. Development 139:1931–1940
Chen L, Fulcoli FG, Ferrentino R et al (2012) Transcriptional control in cardiac progenitors: Tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a. PLoS Genet 8:e1002571
Sinha T, Li D, Theveniau-Ruissy M, Hutson MR et al (2014) Loss of Wnt5a disrupts second heart field cell deployment and may contribute to OFT malformations in DiGeorge syndrome. Hum Mol Genet 24:1704–1716
Conway SJ, Henderson DJ, Kirby ML et al (1997) Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc Res 36:163–173
Mesbah K, Harrelson Z, Theveniau-Ruissy M et al (2008) Tbx3 is required for outflow tract development. Circ Res 103:743–750
Bakker ML, Boukens BJ, Mommersteeg MT et al (2008) Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system. Circ Res 102:1340–1349
Stankunas K, Shang C, Twu KY et al (2008) Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease. Circ Res 103:702–709
Chang CP, Stankunas K, Shang C et al (2008) Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract. Development 135:3577–3586
Bostrom MP, Hutchins GM (1988) Arrested rotation of the outflow tract may explain double-outlet right ventricle. Circulation 77:1258–1265
Lomonico MP, Bostrom MP, Moore GW et al (1988) Arrested rotation of the outflow tract may explain tetralogy of Fallot and transposition of the great arteries. Pediatr Pathol 8:267–281
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
Thompson RP, Abercrombie V, Wong M (1987) Morphogenesis of the truncus arteriosus of the chick embryo heart: movements of autoradiographic tattoos during septation. Anat Rec 218:434–440, 394–435
Bajolle F, Zaffran S, Meilhac SM et al (2008) Myocardium at the base of the aorta and pulmonary trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field. Dev Biol 313:25–34
Vandenberg LN, Levin M (2013) A unified model for left-right asymmetry? Comparison and synthesis of molecular models of embryonic laterality. Dev Biol 379:1–15
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
Morishima M, Yasui H, Nakazawa M et al (1998) Situs variation and cardiovascular anomalies in the transgenic mouse insertional mutation, inv. Teratology 57:302–309
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
Weninger WJ, Lopes Floro K, 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
Tan SY, Rosenthal J, Zhao XQ et al (2007) Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia. J Clin Invest 117:3742–3752
Willaredt MA, Gorgas K, Gardner HA et al (2012) Multiple essential roles for primary cilia in heart development. Cilia 1:23
Franco D, Christoffels VM, Campione M (2014) Homeobox transcription factor Pitx2: the rise of an asymmetry gene in cardiogenesis and arrhythmogenesis. Trends Cardiovasc Med 24:23–31
Scherptong RW, Jongbloed MR, Wisse LJ et al (2012) Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept. Dev Dyn 241:1413–1422
Nowotschin S, Liao J, Gage PJ et al (2006) Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 133(8):1565–1573
Garside VC, Chang AC, Karsan A et al (2013) Co-ordinating Notch, BMP, and TGF-beta signaling during heart valve development. Cell Mol Life Sci 70:2899–2917
Bartram U, Molin DG, Wisse LJ et al (2001) Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice. Circulation 103:2745–2752
Midgett M, Rugonyi S (2014) Congenital heart malformations induced by hemodynamic altering surgical interventions. Front Physiol 5:287
Yashiro K, Shiratori H, Hamada H (2007) Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 450:285–288
Van Praagh R, Van Praagh S (1966) Isolated ventricular inversion. A consideration of the morphogenesis, definition and diagnosis of nontransposed and transposed great arteries. Am J Cardiol 17:395–406
Goor DA, Edwards JE (1973) The spectrum of transposition of the great arteries: with specific reference to developmental anatomy of the conus. Circulation 48:406–415
Restivo A, Piacentini G, Placidi S et al (2006) Cardiac outflow tract: a review of some embryogenetic aspects of the conotruncal region of the heart. Anat Rec A Discov Mol Cell Evol Biol 288:936–943
Tullio AN, Accili D, Ferrans VJ et al (1997) Nonmuscle myosin II-B is required for normal development of the mouse heart. Proc Natl Acad Sci U S A 94:12407–12412
Schaefer KS, Doughman YQ, Fisher SA et al (2004) Dynamic patterns of apoptosis in the developing chicken heart. Dev Dyn 229:489–499
Watanabe M, Jafri A, Fisher SA (2001) Apoptosis is required for the proper formation of the ventriculo-arterial connections. Dev Biol 240:274–288
Molin DG, Roest PA, Nordstrand H et al (2004) Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats. Birth Defects Res A Clin Mol Teratol 70:927–938
Acknowledgements
Research in the author’s laboratory is supported by the Agence Nationale pour la Recherche, Fondation pour la Recherche Médicale and Association Française contre les Myopathies.
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Kelly, R.G. (2016). Molecular Pathways and Animal Models of Tetralogy of Fallot and Double Outlet Right Ventricle. 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_33
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DOI: https://doi.org/10.1007/978-3-7091-1883-2_33
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