Skip to main content

Advertisement

SpringerLink
Log in

The second heart field: the first 20 years

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

In 2001, three independent groups reported the identification of a novel cluster of progenitor cells that contribute to heart development in mouse and chicken embryos. This population of progenitor cells was designated as the second heart field (SHF), and a new research direction in heart development was launched. Twenty years have since passed and a comprehensive understanding of the SHF has been achieved. This review provides retrospective insights in to the contribution, the signaling regulatory networks and the epithelial properties of the SHF. It also includes the spatiotemporal characteristics of SHF development and interactions between the SHF and other types of cells during heart development. Although considerable efforts will be required to investigate the cellular heterogeneity of the SHF, together with its intricate regulatory networks and undefined mechanisms, it is expected that the burgeoning new technology of single-cell sequencing and precise lineage tracing will advance the comprehension of SHF function and its molecular signals. The advances in SHF research will translate to clinical applications and to the treatment of congenital heart diseases, especially conotruncal defects, as well as to regenerative medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Anderson HE, Christiaen L (2016) Ciona as a simple chordate model for heart development and regeneration. J Cardiovasc Dev Dis 3(3):25

    Article  PubMed  Google Scholar 

  • Andersen P, Tampakakis E, Jimenez DV, Kannan S, Miyamoto M, Shin HK, Saberi A, Murphy S, Sulistio E, Chelko SP et al (2018) Precardiac organoids form two heart fields via Bmp/Wnt signaling. Nat Commun 9(1):3140

    Article  PubMed  PubMed Central  Google Scholar 

  • Bagatto B, Francl J, Liu B, Liu Q (2006) Cadherin2 (N-cadherin) plays an essential role in zebrafish cardiovascular development. BMC Dev Biol 6:23

    Article  PubMed  PubMed Central  Google Scholar 

  • Baldini A, Fulcoli FG, Illingworth E (2017) Tbx1: transcriptional and developmental functions. Curr Top Dev Biol 122:223–243

    Article  CAS  PubMed  Google Scholar 

  • Bertrand N, Roux M, Ryckebüsch L, Niederreither K, Dollé P, Moon A, Capecchi M, Zaffran S (2011) Hox genes define distinct progenitor sub-domains within the second heart field. Dev Biol 353(2):266–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs LE, Kakarla J, Wessels A (2012) The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation 84(1):117–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs LE, Phelps AL, Brown E, Kakarla J, Anderson RH, van den Hoff MJ, Wessels A (2013) Expression of the BMP receptor Alk3 in the second heart field is essential for development of the dorsal mesenchymal protrusion and atrioventricular septation. Circ Res 112(11):1420–1432

    Article  CAS  PubMed  Google Scholar 

  • Bryant DM, Mostov KE (2008) From cells to organs: building polarized tissue. Nat Rev Mol Cell Biol 9(11):887–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6(11):826–835

    Article  CAS  PubMed  Google Scholar 

  • Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5(6):877–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caputo L, Witzel HR, Kolovos P, Cheedipudi S, Looso M, Mylona A, van Ijcken WF, Laugwitz KL, Evans SM, Braun T et al (2015) The Isl1/Ldb1 complex orchestrates genome-wide chromatin organization to instruct differentiation of multipotent cardiac progenitors. Cell Stem Cell 17(3):287–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Catón J, Luder HU, Zoupa M, Bradman M, Bluteau G, Tucker AS, Klein O, Mitsiadis TA (2009) Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors. Dev Biol 328(2):493–505

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen L, Fulcoli FG, Tang S, Baldini A (2009) Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circ Res 105(9):842–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Fulcoli FG, Ferrentino R, Martucciello S, Illingworth EA, Baldini A (2012) Transcriptional control in cardiac progenitors: Tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a. PLoS Genet 8(3):e1002571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiapparo G, Lin X, Lescroart F, Chabab S, Paulissen C, Pitisci L, Bondue A, Blanpain C (2016) Mesp1 controls the speed, polarity, and directionality of cardiovascular progenitor migration. J Cell Biol 213(4):463–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhry P, Trede NS (2013) DiGeorge syndrome gene tbx1 functions through wnt11r to regulate heart looping and differentiation. PLoS ONE 8(3):e58145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christoffels VM, Habets PE, Franco D, Campione M, de Jong F, Lamers WH, Bao ZZ, Palmer S, Biben C, Harvey RP et al (2000) Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol 223(2):266–278

    Article  CAS  PubMed  Google Scholar 

  • Christoffels VM, Mommersteeg MT, Trowe MO, Prall OW, de Gier-de Vries C, Soufan AT, Bussen M, Schuster-Gossler K, Harvey RP, Moorman AF et al (2006) Formation of the venous pole of the heart from an Nkx2-5-negative precursor population requires Tbx18. Circ Res 98(12):1555–1563

    Article  CAS  PubMed  Google Scholar 

  • Cohen ED, Wang Z, Lepore JJ, Lu MM, Taketo MM, Epstein DJ, Morrisey EE (2007) Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. J Clin Invest 117(7):1794–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen ED, Miller MF, Wang Z, Moon RT, Morrisey EE (2012) Wnt5a and Wnt11 are essential for second heart field progenitor development. Development 139(11):1931–1940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colombo S, de Sena-Tomás C, George V, Werdich AA, Kapur S, MacRae CA, Targoff KL (2018) Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression. Development 145(3):dev161497

    PubMed  PubMed Central  Google Scholar 

  • Cota CD, Davidson B (2015) Mitotic membrane turnover coordinates differential induction of the heart progenitor lineage. Dev Cell 34(5):505–519

    Article  CAS  PubMed  Google Scholar 

  • de la Cruz MV, Sánchez Gómez C, Arteaga MM, Argüello C (1977) Experimental study of the development of the truncus and the conus in the chick embryo. J Anat 123(Pt 3):661–686

    PubMed  PubMed Central  Google Scholar 

  • de Pater E, Clijsters L, Marques SR, Lin YF, Garavito-Aguilar ZV, Yelon D, Bakkers J (2009) Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart. Development 136(10):1633–1641

    Article  PubMed  PubMed Central  Google Scholar 

  • DeLaughter DM, Bick AG, Wakimoto H, McKean D, Gorham JM, Kathiriya IS, Hinson JT, Homsy J, Gray J, Pu W et al (2016) Single-cell resolution of temporal gene expression during heart development. Dev Cell 39(4):480–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Desgrange A, Le Garrec JF, Bernheim S, Bønnelykke TH, Meilhac SM (2020) Transient nodal signaling in left precursors coordinates opposed asymmetries shaping the heart loop. Dev Cell 55(4):413-431.e6

    Article  CAS  PubMed  Google Scholar 

  • Devine WP, Wythe JD, George M, Koshiba-Takeuchi K, Bruneau BG (2014) Early patterning and specification of cardiac progenitors in gastrulating mesoderm. Elife 3:e03848

    Article  PubMed  PubMed Central  Google Scholar 

  • Diogo R, Kelly RG, Christiaen L, Levine M, Ziermann JM, Molnar JL, Noden DM, Tzahor E (2015) A new heart for a new head in vertebrate cardiopharyngeal evolution. Nature 520(7548):466–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dodou E, Verzi MP, Anderson JP, Xu SM, Black BL (2004) Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development 131(16):3931–3942

    Article  CAS  PubMed  Google Scholar 

  • Domínguez JN, Meilhac SM, Bland YS, Buckingham ME, Brown NA (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(10):1323–1335

    Article  PubMed  Google Scholar 

  • Dorn T, Goedel A, Lam JT, Haas J, Tian Q, Herrmann F, Bundschu K, Dobreva G, Schiemann M, Dirschinger R et al (2015) Direct nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity. Stem Cells 33(4):1113–1129

    Article  CAS  PubMed  Google Scholar 

  • Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (1997) The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. Embo j 16(18):5687–5696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dyer LA, Kirby ML (2009a) The role of secondary heart field in cardiac development. Dev Biol 336(2):137–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dyer LA, Kirby ML (2009b) Sonic hedgehog maintains proliferation in secondary heart field progenitors and is required for normal arterial pole formation. Dev Biol 330(2):305–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engleka KA, Manderfield LJ, Brust RD, Li L, Cohen A, Dymecki SM, Epstein JA (2012) Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 110(7):922–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Epstein JA, Franklin H. Epstein Lecture (2010) Cardiac development and implications for heart disease. N Engl J Med 363(17):1638–1647

    Article  CAS  PubMed  Google Scholar 

  • Francou A, Saint-Michel E, Mesbah K, Kelly RG (2014) TBX1 regulates epithelial polarity and dynamic basal filopodia in the second heart field. Development 141(22):4320–4331

    Article  CAS  PubMed  Google Scholar 

  • Francou A, De Bono C, Kelly RG (2017) Epithelial tension in the second heart field promotes mouse heart tube elongation. Nat Commun 8:14770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii M, Sakaguchi A, Kamata R, Nagao M, Kikuchi Y, Evans SM, Yoshizumi M, Shimono A, Saga Y, Kokubo H (2017) Sfrp5 identifies murine cardiac progenitors for all myocardial structures except for the right ventricle. Nat Commun 8:14664

    Article  PubMed  PubMed Central  Google Scholar 

  • Fulcoli FG, Franzese M, Liu X, Zhang Z, Angelini C, Baldini A (2016) Rebalancing gene haploinsufficiency in vivo by targeting chromatin. Nat Commun 7:11688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furtado MB, Biben C, Shiratori H, Hamada H, Harvey RP (2011) Characterization of Pitx2c expression in the mouse heart using a reporter transgene. Dev Dyn 240(1):195–203

    Article  CAS  PubMed  Google Scholar 

  • Galli D, Domínguez JN, Zaffran S, Munk A, Brown NA, Buckingham ME (2008) Atrial myocardium derives from the posterior region of the second heart field, which acquires left-right identity as Pitx2c is expressed. Development 135(6):1157–1167

    Article  CAS  PubMed  Google Scholar 

  • Garg V, Yamagishi C, Hu T, Kathiriya IS, Yamagishi H, Srivastava D (2001) Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev Biol 235(1):62–73

    Article  CAS  PubMed  Google Scholar 

  • Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K et al (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424(6947):443–447

    Article  CAS  PubMed  Google Scholar 

  • Gaspar P, Tapon N (2014) Sensing the local environment: actin architecture and Hippo signalling. Curr Opin Cell Biol 31:74–83

    Article  CAS  PubMed  Google Scholar 

  • Gessert S, Kühl M (2009) Comparative gene expression analysis and fate mapping studies suggest an early segregation of cardiogenic lineages in Xenopus laevis. Dev Biol 334(2):395–408

    Article  CAS  PubMed  Google Scholar 

  • Gibbs BC, Damerla RR, Vladar EK, Chatterjee B, Wan Y, Liu X, Cui C, Gabriel GC, Zahid M, Yagi H et al (2016) Prickle1 mutation causes planar cell polarity and directional cell migration defects associated with cardiac outflow tract anomalies and other structural birth defects. Biol Open 5(3):323–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gibson WT, Veldhuis JH, Rubinstein B, Cartwright HN, Perrimon N, Brodland GW, Nagpal R, Gibson MC (2011) Control of the mitotic cleavage plane by local epithelial topology. Cell 144(3):427–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goddeeris MM, Rho S, Petiet A, Davenport CL, Johnson GA, Meyers EN, Klingensmith J (2008) Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart. Development 135(10):1887–1895

    Article  CAS  PubMed  Google Scholar 

  • Grifone R, Kelly RG (2007) Heartening news for head muscle development. Trends Genet 23(8):365–369

    Article  CAS  PubMed  Google Scholar 

  • Guo C, Sun Y, Zhou B, Adam RM, Li X, Pu WT, Morrow BE, Moon A, Li X (2011) A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. J Clin Invest 121(4):1585–1595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guris DL, Duester G, Papaioannou VE, Imamoto A (2006) Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell 10(1):81–92

    Article  CAS  PubMed  Google Scholar 

  • Hami D, Grimes AC, Tsai HJ, Kirby ML (2011) Zebrafish cardiac development requires a conserved secondary heart field. Development 138(11):2389–2398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harvey RP (2002) Patterning the vertebrate heart. Nat Rev Genet 3(7):544–556

    Article  CAS  PubMed  Google Scholar 

  • He Z, Grunewald M, Dor Y, Keshet E (2016) VEGF regulates relative allocation of Isl1(+) cardiac progenitors to myocardial and endocardial lineages. Mech Dev 142:40–49

    Article  CAS  PubMed  Google Scholar 

  • Heisenberg CP, Bellaïche Y (2013) Forces in tissue morphogenesis and patterning. Cell 153(5):948–962

    Article  CAS  PubMed  Google Scholar 

  • High FA, Jain R, Stoller JZ, Antonucci NB, Lu MM, Loomes KM, Kaestner KH, Pear WS, Epstein JA (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(7):1986–1996

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffmann AD, Peterson MA, Friedland-Little JM, Anderson SA, Moskowitz IP (2009) sonic hedgehog is required in pulmonary endoderm for atrial septation. Development 136(10):1761–1770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffmann AD, Yang XH, Burnicka-Turek O, Bosman JD, Ren X, Steimle JD, Vokes SA, McMahon AP, Kalinichenko VV, Moskowitz IP (2014) Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet 10(10):e1004604

    Article  PubMed  PubMed Central  Google Scholar 

  • Hutson MR, Zeng XL, Kim AJ, Antoon E, Harward S, Kirby ML (2010) Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate. Development 137(18):3001–3011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huynh T, Chen L, Terrell P, Baldini A (2007) A fate map of Tbx1 expressing cells reveals heterogeneity in the second cardiac field. Genesis 45(7):470–475

    Article  CAS  PubMed  Google Scholar 

  • Ilagan R, Abu-Issa R, Brown D, Yang YP, Jiao K, Schwartz RJ, Klingensmith J, Meyers EN (2006) Fgf8 is required for anterior heart field development. Development 133(12):2435–2445

    Article  CAS  PubMed  Google Scholar 

  • Ivanovitch K, Temiño S, Torres M (2017) Live imaging of heart tube development in mouse reveals alternating phases of cardiac differentiation and morphogenesis. Elife 6:e30668

    Article  PubMed  PubMed Central  Google Scholar 

  • Jahangiri L, Sharpe M, Novikov N, González-Rosa JM, Borikova A, Nevis K, Paffett-Lugassy N, Zhao L, Adams M, Guner-Ataman B et al (2016) The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field. Development 143(1):113–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain R, Li D, Gupta M, Manderfield LJ, Ifkovits JL, Wang Q, Liu F, Liu Y, Poleshko A, Padmanabhan A et al (2015) HEART DEVELOPMENT. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Science 348(6242):aaa6071

    Article  PubMed  PubMed Central  Google Scholar 

  • Jin H, Wang H, Li J, Yu S, Xu M, Qiu Z, Xia M, Zhu J, Feng Q, Xie J et al (2019) Differential contribution of the two waves of cardiac progenitors and their derivatives to aorta and pulmonary artery. Dev Biol 450(2):82–89

    Article  CAS  PubMed  Google Scholar 

  • Kang J, Nathan E, Xu SM, Tzahor E, Black BL (2009) Isl1 is a direct transcriptional target of Forkhead transcription factors in second-heart-field-derived mesoderm. Dev Biol 334(2):513–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kappen C, Salbaum JM (2009) Identification of regulatory elements in the Isl1 gene locus. Int J Dev Biol 53(7):935–946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelly RG (2012) The second heart field. Curr Top Dev Biol 100:33–65

    Article  CAS  PubMed  Google Scholar 

  • Kelly RG, Buckingham ME (2002) The anterior heart-forming field: voyage to the arterial pole of the heart. Trends Genet 18(4):210–216

    Article  CAS  PubMed  Google Scholar 

  • Kelly RG, Papaioannou VE (2007) Visualization of outflow tract development in the absence of Tbx1 using an FgF10 enhancer trap transgene. Dev Dyn 236(3):821–828

    Article  CAS  PubMed  Google Scholar 

  • Kelly RG, Brown NA, Buckingham ME (2001) The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 1(3):435–440

    Article  CAS  PubMed  Google Scholar 

  • Kelly RG, Buckingham ME, Moorman AF (2014) Heart fields and cardiac morphogenesis. Cold Spring Harb Perspect Med 4(10):a015750

    Article  PubMed  PubMed Central  Google Scholar 

  • Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S et al (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152(3):570–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11(8):951–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M et al (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433(7026):647–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lazic S, Scott IC (2011) Mef2cb regulates late myocardial cell addition from a second heart field-like population of progenitors in zebrafish. Dev Biol 354(1):123–133

    Article  CAS  PubMed  Google Scholar 

  • Le Garrec JF, Domínguez JN, Desgrange A, Ivanovitch KD, Raphaël E, Bangham JA, Torres M, Coen E, Mohun TJ, Meilhac SM (2017) A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics. Elife 6:e28951

    Article  PubMed  PubMed Central  Google Scholar 

  • Lescroart F, Kelly RG, Le Garrec JF, Nicolas JF, Meilhac SM, Buckingham M (2010) Clonal analysis reveals common lineage relationships between head muscles and second heart field derivatives in the mouse embryo. Development 137(19):3269–3279

    Article  CAS  PubMed  Google Scholar 

  • Lescroart F, Mohun T, Meilhac SM, Bennett M, Buckingham M (2012) Lineage tree for the venous pole of the heart: clonal analysis clarifies controversial genealogy based on genetic tracing. Circ Res 111(10):1313–1322

    Article  CAS  PubMed  Google Scholar 

  • Lescroart F, Chabab S, Lin X, Rulands S, Paulissen C, Rodolosse A, Auer H, Achouri Y, Dubois C, Bondue A et al (2014) Early lineage restriction in temporally distinct populations of Mesp1 progenitors during mammalian heart development. Nat Cell Biol 16(9):829–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lescroart F, Wang X, Lin X, Swedlund B, Gargouri S, Sànchez-Dànes A, Moignard V, Dubois C, Paulissen C, Kinston S et al (2018) Defining the earliest step of cardiovascular lineage segregation by single-cell RNA-seq. Science 359(6380):1177–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(3):480–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR et al (2015) Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 521(7553):520–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Sinha T, Ajima R, Seo HS, Yamaguchi TP, Wang J (2016a) Spatial regulation of cell cohesion by Wnt5a during second heart field progenitor deployment. Dev Biol 412(1):18–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li G, Xu A, Sim S, Priest JR, Tian X, Khan T, Quertermous T, Zhou B, Tsao PS, Quake SR et al (2016b) Transcriptomic profiling maps anatomically patterned subpopulations among single embryonic cardiac cells. Dev Cell 39(4):491–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao J, Aggarwal VS, Nowotschin S, Bondarev A, Lipner S, Morrow BE (2008) Identification of downstream genetic pathways of Tbx1 in the second heart field. Dev Biol 316(2):524–537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liberatore CM, Searcy-Schrick RD, Vincent EB, Yutzey KE (2002) Nkx-2.5 gene induction in mice is mediated by a Smad consensus regulatory region. Dev Biol 244(2):243–256

    Article  CAS  PubMed  Google Scholar 

  • Lien CL, McAnally J, Richardson JA, Olson EN (2002) Cardiac-specific activity of an Nkx2-5 enhancer requires an evolutionarily conserved Smad binding site. Dev Biol 244(2):257–266

    Article  CAS  PubMed  Google Scholar 

  • Lin L, Bu L, Cai CL, Zhang X, Evans S (2006) Isl1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis. Dev Biol 295(2):756–763

    Article  CAS  PubMed  Google Scholar 

  • Lin L, Cui L, Zhou W, Dufort D, Zhang X, Cai CL, Bu L, Yang L, Martin J, Kemler R et al (2007) Beta-catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis. Proc Natl Acad Sci USA 104(22):9313–9318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin CY, Lin CJ, Chen CH, Chen RM, Zhou B, Chang CP (2012) The secondary heart field is a new site of calcineurin/Nfatc1 signaling for semilunar valve development. J Mol Cell Cardiol 52(5):1096–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linask KK, Han M, Cai DH, Brauer PR, Maisastry SM (2005) Cardiac morphogenesis: matrix metalloproteinase coordination of cellular mechanisms underlying heart tube formation and directionality of looping. Dev Dyn 233(3):739–753

    Article  CAS  PubMed  Google Scholar 

  • Lioux G, Liu X, Temiño S, Oxendine M, Ayala E, Ortega S, Kelly RG, Oliver G, Torres M (2020) A second heart field-derived vasculogenic niche contributes to cardiac lymphatics. Dev Cell 52(3):350-363.e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(21):5081–5091

    Article  CAS  PubMed  Google Scholar 

  • Luo W, Zhao X, Jin H, Tao L, Zhu J, Wang H, Hemmings BA, Yang Z (2015) Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development. Development 142(4):732–742

    Article  CAS  PubMed  Google Scholar 

  • Ma Q, Zhou B, Pu WT (2008) Reassessment of Isl1 and Nkx2-5 cardiac fate maps using a Gata4-based reporter of Cre activity. Dev Biol 323(1):98–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marguerie A, Bajolle F, Zaffran S, Brown NA, Dickson C, Buckingham ME, Kelly RG (2006) Congenital heart defects in Fgfr2-IIIb and Fgf10 mutant mice. Cardiovasc Res 71(1):50–60

    Article  CAS  PubMed  Google Scholar 

  • Meilhac SM, Buckingham ME (2018) The deployment of cell lineages that form the mammalian heart. Nat Rev Cardiol 15(11):705–724

    Article  PubMed  Google Scholar 

  • Meilhac SM, Esner M, Kelly RG, Nicolas JF, Buckingham ME (2004) The clonal origin of myocardial cells in different regions of the embryonic mouse heart. Dev Cell 6(5):685–698

    Article  CAS  PubMed  Google Scholar 

  • Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, Norris RA, Kern MJ, Eisenberg CA, Turner D, Markwald RR (2001) The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238(1):97–109

    Article  CAS  PubMed  Google Scholar 

  • Mommersteeg MT, Domínguez JN, Wiese C, Norden J, de Gier-de Vries C, Burch JB, Kispert A, Brown NA, Moorman AF, Christoffels VM (2010) The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc Res 87(1):92–101

    Article  CAS  PubMed  Google Scholar 

  • Nachury MV (2014) How do cilia organize signalling cascades? Philos Trans R Soc Lond B Biol Sci 369(1650):20130465

    Article  PubMed  PubMed Central  Google Scholar 

  • Pandur P, Läsche M, Eisenberg LM, Kühl M (2002) Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418(6898):636–641

    Article  CAS  PubMed  Google Scholar 

  • Pane LS, Zhang Z, Ferrentino R, Huynh T, Cutillo L, Baldini A (2012) Tbx1 is a negative modulator of Mef2c. Hum Mol Genet 21(11):2485–2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park EJ, Ogden LA, Talbot A, Evans S, Cai CL, Black BL, Frank DU, Moon AM (2006) Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development 133(12):2419–2433

    Article  CAS  PubMed  Google Scholar 

  • Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H et al (2007) An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128(5):947–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M, Hynes RO (1997) Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181(1):64–78

    Article  CAS  PubMed  Google Scholar 

  • Ramsbottom SA, Sharma V, Rhee HJ, Eley L, Phillips HM, Rigby HF, Dean C, Chaudhry B, Henderson DJ (2014) Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development. PLoS Genet 10(12):e1004871

    Article  PubMed  PubMed Central  Google Scholar 

  • Rana MS, Théveniau-Ruissy M, De Bono C, Mesbah K, Francou A, Rammah M, Domínguez JN, Roux M, Laforest B, Anderson RH 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(9):790–799

    Article  CAS  PubMed  Google Scholar 

  • Rawles ME (1943) The heart-forming areas of the early chick blastoderm. Physiol Zool 16:22–43

    Article  Google Scholar 

  • Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, Cohn I, Curtis M, Dhir P, Hayeems RZ et al (2020) The cardiac genome clinic: implementing genome sequencing in pediatric heart disease. Genet Med 22(6):1015–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts C, Ivins SM, James CT, Scambler PJ (2005) Retinoic acid down-regulates Tbx1 expression in vivo and in vitro. Dev Dyn 232(4):928–938

    Article  CAS  PubMed  Google Scholar 

  • Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104(8):933–942

    Article  CAS  PubMed  Google Scholar 

  • Rones MS, McLaughlin KA, Raffin M, Mercola M (2000) Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis. Development 127(17):3865–3876

    Article  CAS  PubMed  Google Scholar 

  • Ryckebusch L, Wang Z, Bertrand N, Lin SC, Chi X, Schwartz R, Zaffran S, Niederreither K (2008) Retinoic acid deficiency alters second heart field formation. Proc Natl Acad Sci USA 105(8):2913–2918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryckebüsch L, Bertrand N, Mesbah K, Bajolle F, Niederreither K, Kelly RG, Zaffran S (2010) Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circ Res 106(4):686–694

    Article  PubMed  PubMed Central  Google Scholar 

  • Rydeen AB, Waxman JS (2016) Cyp26 enzymes facilitate second heart field progenitor addition and maintenance of ventricular integrity. PLoS Biol 14(11):e2000504

    Article  PubMed  PubMed Central  Google Scholar 

  • Seo S, Kume T (2006) Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev Biol 296(2):421–436

    Article  CAS  PubMed  Google Scholar 

  • Shenje LT, Andersen P, Uosaki H, Fernandez L, Rainer PP, Cho GS, Lee DI, Zhong W, Harvey RP, Kass DA et al (2014) Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors. Elife 3:e02164

    Article  PubMed  PubMed Central  Google Scholar 

  • Shinohara K, Hamada H (2017) Cilia in left-right symmetry breaking. Cold Spring Harb Perspect Biol 9(10):a028282

    Article  PubMed  PubMed Central  Google Scholar 

  • Sirbu IO, Zhao X, Duester G (2008) Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8 pathway. Dev Dyn 237(6):1627–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snarr BS, O’Neal JL, Chintalapudi MR, Wirrig EE, Phelps AL, Kubalak SW, Wessels A (2007a) Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res 101(10):971–974

    Article  CAS  PubMed  Google Scholar 

  • Snarr BS, Wirrig EE, Phelps AL, Trusk TC, Wessels A (2007b) A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn 236(5):1287–1294

    Article  PubMed  PubMed Central  Google Scholar 

  • Soh BS, Buac K, Xu H, Li E, Ng SY, Wu H, Chmielowiec J, Jiang X, Bu L, Li RA et al (2014) N-cadherin prevents the premature differentiation of anterior heart field progenitors in the pharyngeal mesodermal microenvironment. Cell Res 24(12):1420–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song YC, Dohn TE, Rydeen AB, Nechiporuk AV, Waxman JS (2019) HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development. PLoS Genet 15(5):e1008165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanley EG, Biben C, Elefanty A, Barnett L, Koentgen F, Robb L, Harvey RP (2002) Efficient Cre-mediated deletion in cardiac progenitor cells conferred by a 3’UTR-ires-Cre allele of the homeobox gene Nkx2-5. Int J Dev Biol 46(4):431–439

    CAS  PubMed  Google Scholar 

  • Stolfi A, Gainous TB, Young JJ, Mori A, Levine M, Christiaen L (2010) Early chordate origins of the vertebrate second heart field. Science 329(5991):565–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeichi M (2014) Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol 15(6):397–410

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi JK, Bruneau BG (2009) Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459(7247):708–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Théveniau-Ruissy M, Dandonneau M, Mesbah K, Ghez O, Mattei MG, Miquerol L, Kelly RG (2008) The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning. Circ Res 103(2):142–148

    Article  PubMed  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  CAS  PubMed  Google Scholar 

  • Tian Y, Yuan L, Goss AM, Wang T, Yang J, Lepore JJ, Zhou D, Schwartz RJ, Patel V, Cohen ED et al (2010) Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. Dev Cell 18(2):275–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tirosh-Finkel L, Zeisel A, Brodt-Ivenshitz M, Shamai A, Yao Z, Seger R, Domany E, Tzahor E (2010) BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. Development 137(18):2989–3000

    Article  CAS  PubMed  Google Scholar 

  • Toomer KA, Fulmer D, Guo L, Drohan A, Peterson N, Swanson P, Brooks B, Mukherjee R, Body S, Lipschutz JH et al (2017) A role for primary cilia in aortic valve development and disease. Dev Dyn 246(8):625–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van den Berg G, Abu-Issa R, de Boer BA, Hutson MR, de Boer PA, Soufan AT, Ruijter JM, Kirby ML, van den Hoff MJ, Moorman AF (2009) A caudal proliferating growth center contributes to both poles of the forming heart tube. Circ Res 104(2):179–188

    Article  PubMed  Google Scholar 

  • Van der Heiden K, Groenendijk BC, Hierck BP, Hogers B, Koerten HK, Mommaas AM, Gittenberger-de Groot AC, Poelmann RE (2006) Monocilia on chicken embryonic endocardium in low shear stress areas. Dev Dyn 235(1):19–28

    Article  PubMed  Google Scholar 

  • 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 12(1):19–38

    Article  Google Scholar 

  • Verzi MP, McCulley DJ, De Val S, Dodou E, Black BL (2005) The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev Biol 287(1):134–145

    Article  CAS  PubMed  Google Scholar 

  • Vincent SD, Buckingham ME (2010) How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 90:1–41

    Article  PubMed  Google Scholar 

  • von Both I, Silvestri C, Erdemir T, Lickert H, Walls JR, Henkelman RM, Rossant J, Harvey RP, Attisano L, Wrana JL (2004) Foxh1 is essential for development of the anterior heart field. Dev Cell 7(3):331–345

    Article  Google Scholar 

  • Waldo KL, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH, Kirby ML (2001) Conotruncal myocardium arises from a secondary heart field. Development 128(16):3179–3188

    Article  CAS  PubMed  Google Scholar 

  • Waldo KL, Hutson MR, Stadt HA, Zdanowicz M, Zdanowicz J, Kirby ML (2005a) Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field. Dev Biol 281(1):66–77

    Article  CAS  PubMed  Google Scholar 

  • Waldo KL, Hutson MR, Ward CC, Zdanowicz M, Stadt HA, Kumiski D, Abu-Issa R, Kirby ML (2005b) Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart. Dev Biol 281(1):78–90

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Razy-Krajka F, Siu E, Ketcham A, Christiaen L (2013) NK4 antagonizes Tbx1/10 to promote cardiac versus pharyngeal muscle fate in the ascidian second heart field. PLoS Biol 11(12):e1001725

    Article  PubMed  PubMed Central  Google Scholar 

  • Watanabe Y, Miyagawa-Tomita S, Vincent SD, Kelly RG, Moon AM, Buckingham ME (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(3):495–503

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Zaffran S, Kuroiwa A, Higuchi H, Ogura T, Harvey RP, Kelly RG, Buckingham M (2012) Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium. Proc Natl Acad Sci USA 109(45):18273–18280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Witzel HR, Jungblut B, Choe CP, Crump JG, Braun T, Dobreva G (2012) The LIM protein Ajuba restricts the second heart field progenitor pool by regulating Isl1 activity. Dev Cell 23(1):58–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wyatt TP, Harris AR, Lam M, Cheng Q, Bellis J, Dimitracopoulos A, Kabla AJ, Charras GT, Baum B (2015) Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc Natl Acad Sci USA 112(18):5726–5731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia M, Luo W, Jin H, Yang Z (2019) HAND2-mediated epithelial maintenance and integrity in cardiac outflow tract morphogenesis. Development 146(13):dev177477

    Article  CAS  PubMed  Google Scholar 

  • Xie L, Hoffmann AD, Burnicka-Turek O, Friedland-Little JM, Zhang K, Moskowitz IP (2012) Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell 23(2):280–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue Z, Hennelly S, Doyle B, Gulati AA, Novikova IV, Sanbonmatsu KY, Boyer LA (2016) A G-Rich Motif in the lncRNA braveheart interacts with a Zinc-Finger transcription factor to specify the cardiovascular lineage. Mol Cell 64(1):37–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan X, Qi H, Li X, Wu F, Fang J, Bober E, Dobreva G, Zhou Y, Braun T (2017) Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice. J Clin Invest 127(6):2235–2248

    Article  PubMed  PubMed Central  Google Scholar 

  • Zaffran S, Kelly RG, Meilhac SM, Buckingham ME, Brown NA (2004) Right ventricular myocardium derives from the anterior heart field. Circ Res 95(3):261–268

    Article  CAS  PubMed  Google Scholar 

  • Zeng XX, Yelon D (2014) Cadm4 restricts the production of cardiac outflow tract progenitor cells. Cell Rep 7(4):951–960

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Tao R, Campbell KF, Carvalho JL, Ruiz EC, Kim GC, Schmuck EG, Raval AN, da Rocha AM, Herron TJ et al (2019) Functional cardiac fibroblasts derived from human pluripotent stem cells via second heart field progenitors. Nat Commun 10(1):2238

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Cashman TJ, Nevis KR, Obregon P, Carney SA, Liu Y, Gu A, Mosimann C, Sondalle S, Peterson RE et al (2011) Latent TGF-β binding protein 3 identifies a second heart field in zebrafish. Nature 474(7353):645–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Liu J, Olson P, Zhang K, Wynne J, Xie L (2015) Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. J Mol Cell Cardiol 85:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Liu J, Xiang M, Olson P, Guzzetta A, Zhang K, Moskowitz IP, Xie L (2017a) Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation. Proc Natl Acad Sci USA 114(8):E1422-e1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Z, Wang J, Guo C, Chang W, Zhuang J, Zhu P, Li X (2017b) Temporally distinct six2-positive second heart field progenitors regulate mammalian heart development and disease. Cell Rep 18(4):1019–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31930029 and 91854111) and from the National Key Research and Development Program of China (2019YFA0801601) to Zhongzhou Yang

Author information

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, 210093, China

    Ke Zhao & Zhongzhou Yang

Authors
  1. Ke Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongzhou Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KZ. wrote the draft and ZY. corrected and edited.

Corresponding author

Correspondence to Zhongzhou Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, K., Yang, Z. The second heart field: the first 20 years. Mamm Genome 34, 216–228 (2023). https://doi.org/10.1007/s00335-022-09975-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-022-09975-8

Search

Navigation