Zebrafish Heart Development: Comparison
Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Joshua Waxman.

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of the heart. Zebrafish are an outstanding model for studying vertebrate cardiogenesis, due to the conservation of molecular mechanisms underlying early heart development, external development, and ease of genetic manipulation.

  • zebrafish
  • heart development
  • atrium
  • sinoatrial node
  • congenital heart defects
Please wait, diff process is still running!

References

  1. Al Turki, S.; Manickaraj, A.K.; Mercer, C.L.; Gerety, S.S.; Hitz, M.P.; Lindsay, S.; D’Alessandro, L.C.A.; Swaminathan, G.J.; Bentham, J.; Arndt, A.K.; et al. Rare variants in NR2F2 cause congenital heart defects in humans. Am. J. Hum. Genet. 2014, 94, 574–585.
  2. Nakamura, E.; Makita, Y.; Okamoto, T.; Nagaya, K.; Hayashi, T.; Sugimoto, M.; Manabe, H.; Taketazu, G.; Kajino, H.; Fujieda, K. 5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects. Eur. J. Med. Genet. 2011, 54, 354–356.
  3. Benson, D.W.; Silberbach, G.M.; Kavanaugh-McHugh, A.; Cottrill, C.; Zhang, Y.; Riggs, S.; Smalls, O.; Johnson, M.C.; Watson, M.S.; Seidman, J.G.; et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J. Clin. Investig. 1999, 104, 1567–1573.
  4. Schott, J.J.; Benson, D.W.; Basson, C.T.; Pease, W.; Silberbach, G.M.; Moak, J.P.; Maron, B.J.; Seidman, C.E.; Seidman, J.G. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 1998, 281, 108–111.
  5. Hoffman, J.I.E.; Kaplan, S. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 2002, 39, 1890–1900.
  6. Loffredo, C.A. Epidemiology of cardiovascular malformations: Prevalence and risk factors. Am. J. Med. Genet. 2000, 97, 319–325.
  7. Van der Linde, D.; Konings, E.E.M.; Slager, M.A.; Witsenburg, M.; Helbing, W.A.; Takkenberg, J.J.M.; Roos-Hesselink, J.W. Birth prevalence of congenital heart disease worldwide. J. Am. Coll. Cardiol. 2011, 58, 2241–2247.
  8. Benjamin, E.J.; Virani, S.S.; Callaway, C.W.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Chiuve, S.E.; Cushman, M.; Delling, F.N.; Deo, R.; et al. Heart disease and stroke statistics-2018 update: A report from the American Heart Association. Circulation 2018, 137, E67–E492.
  9. Marelli, A.J.; Mackie, A.S.; Ionescu-Ittu, R.; Rahme, E.; Pilote, L. Congenital heart disease in the general population: Changing prevalence and age distribution. Circulation 2007, 115, 163–172.
  10. Bruneau, B.G.; Logan, M.; Davis, N.; Levi, T.; Tabin, C.J.; Seidman, J.G.; Seidman, C.E. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt- Oram syndrome. Dev. Biol. 1999, 211, 100–108.
  11. John, R.M.; Kumar, S. Sinus node and atrial arrhythmias. Circulation 2016, 133, 1892–1900.
  12. Choudhury, M.; Boyett, M.R.; Morris, G.M. Biology of the sinus node and its disease. Arrhythmia Electrophysiol. Rev. 2015, 4, 28–34.
  13. Hoffmann, S.; Paone, C.; Sumer, S.A.; Diebold, S.; Weiss, B.; Roeth, R.; Clauss, S.; Klier, I.; Kääb, S.; Schulz, A.; et al. Functional characterization of rare variants in the SHOX2 gene identified in sinus node dysfunction and atrial fibrillation. Front. Genet. 2019, 10.
  14. Milanesi, R.; Baruscotti, M.; Gnecchi-Ruscone, T.; DiFrancesco, D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N. Engl. J. Med. 2006, 354, 151–157.
  15. Jhaveri, S.; Aziz, P.F.; Saarel, E. Expanding the electrical phenotype of NKX2-5 mutations: Ventricular tachycardia, atrial fibrillation, and complete heart block within one family. Hear. Case Rep. 2018, 4, 530–533.
  16. Vornanen, M.; Hassinen, M. Zebrafish heart as a model for human cardiac electrophysiology. Channels 2016, 10, 101–110.
  17. Giardoglou, P.; Beis, D. On zebrafish disease models and matters of the heart. Biomedicines 2019, 7, 15.
  18. Bakkers, J. Zebrafish as a model to study cardiac development and human cardiac disease. Cardiovasc. Res. 2011, 91, 279–288.
  19. Brown, D.; Samsa, L.; Qian, L.; Liu, J. Advances in the study of heart development and disease using zebrafish. J. Cardiovasc. Dev. Dis. 2016, 3, 13.
  20. Poon, K.L.; Brand, T. The zebrafish model system in cardiovascular research: A tiny fish with mighty prospects. Glob. Cardiol. Sci. Pract. 2013, 2013, 4.
  21. Ravens, U. Ionic basis of cardiac electrophysiology in zebrafish compared to human hearts. Prog. Biophys. Mol. Biol. 2018, 138, 38–44.
  22. Chi, N.C.; Shaw, R.M.; Jungblut, B.; Huisken, J.; Ferrer, T.; Arnaout, R.; Scott, I.; Beis, D.; Xiao, T.; Baier, H.; et al. Genetic and physiologic dissection of the vertebrate cardiac conduction system. PLoS Biol. 2008, 6, 1006–1019.
  23. Brandenburg, S.; Kohl, T.; Williams, G.S.B.; Gusev, K.; Wagner, E.; Rog-Zielinska, E.A.; Hebisch, E.; Dura, M.; Didié, M.; Gotthardt, M.; et al. Axial tubule junctions control rapid calcium signaling in atria. J. Clin. Investig. 2016, 126, 3999–4015.
  24. Smyrnias, I.; Mair, W.; Harzheim, D.; Walker, S.A.; Roderick, H.L.; Bootman, M.D. Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation-contraction coupling and inotropic stimulation. Cell Calcium 2010, 47, 210–223.
  25. Bloomekatz, J.; Galvez-Santisteban, M.; Chi, N.C. Myocardial plasticity: Cardiac development, regeneration and disease. Curr. Opin. Genet. Dev. 2016, 40, 120–130.
  26. Tessadori, F.; van Weerd, J.H.; Burkhard, S.B.; Verkerk, A.O.; de Pater, E.; Boukens, B.J.; Vink, A.; Christoffels, V.M.; Bakkers, J. Identification and functional characterization of cardiac pacemaker cells in zebrafish. PLoS ONE 2012, 7.
  27. Tabibiazar, R.; Wagner, R.A.; Liao, A.; Quertermous, T. Transcriptional profiling of the heart reveals chamber-specific gene expression patterns. Circ. Res. 2003, 93, 1193–1201.
  28. Ng, S.Y.; Wong, C.K.; Tsang, S.Y. Differential gene expressions in atrial and ventricular myocytes: Insights into the road of applying embryonic stem cell-derived cardiomyocytes for future therapies. Am. J. Physiol. Physiol. 2010, 299, C1234–C1249.
  29. Bootman, M.D.; Higazi, D.R.; Coombes, S.; Roderick, H.L. Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes. J. Cell Sci. 2006, 119, 3915–3925.
  30. Nof, E.; Antzelevitch, C.; Glikson, M. The contribution of HCN4 to normal sinus node function in humans and animal models. Pacing Clin. Electrophysiol. 2010, 33, 100–106.
  31. Christoffels, V.M.; Smits, G.J.; Kispert, A.; Moorman, A.F.M. Development of the pacemaker tissues of the heart. Circ. Res. 2010, 106, 240–254.
  32. Stainier, D.Y.; Lee, R.K.; Fishman, M.C. Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation. Development 1993, 119, 31–40.
  33. Berdougo, E.; Coleman, H.; Lee, D.H.; Stainier, D.Y.R.; Yelon, D. Mutation of weak atrium/atrial myosin heavy chain disrupts atrial function and influences ventricular morphogenesis in zebrafish. Development 2003, 130, 6121–6129.
  34. Staudt, D.; Stainier, D. Uncovering the molecular and cellular mechanisms of heart development using the zebrafish. Annu. Rev. Genet. 2012, 46, 397–418.
  35. Keegan, B.R.; Meyer, D.; Yelon, D. Organization of cardiac chamber progenitors in the zebrafish blastula. Development 2004, 131, 3081–3091.
  36. Yelon, D.; Stainier, D.Y.R. Patterning during organogenesis: Genetic analysis of cardiac chamber formation. Semin. Cell Dev. Biol. 1999, 10, 93–98.
  37. Guerra, A.; Germano, R.F.V.; Stone, O.; Arnaout, R.; Guenther, S.; Ahuja, S.; Uribe, V.; Vanhollebeke, B.; Stainier, D.Y.R.; Reischauer, S. Distinct myocardial lineages break atrial symmetry during cardiogenesis in zebrafish. Elife 2018, 7.
  38. Tessari, A.; Pietrobon, M.; Notte, A.; Cifelli, G.; Gage, P.J.; Schneider, M.D.; Lembo, G.; Campione, M. Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs. Circ. Res. 2008, 102, 813–822.
  39. Rohr, S.; Otten, C.; Abdelilah-Seyfried, S. Asymmetric involution of the myocardial field drives heart tube formation in zebrafish. Circ. Res. 2008, 102.
  40. Yelon, D.; Horne, S.A.; Stainier, D.Y.R. Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish. Dev. Biol. 1999, 214, 23–37.
  41. De Pater, E.; Clijsters, L.; Marques, S.R.; Lin, Y.F.; Garavito-Aguilar, Z.V.; Yelon, D.; Bakkers, J. Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart. Development 2009, 136, 1633–1641.
  42. Liu, J.; Stainier, D.Y.R. Zebrafish in the study of early cardiac development. Circ. Res. 2012, 110, 870–874.
  43. Hami, D.; Grimes, A.C.; Tsai, H.J.; Kirby, M.L. Zebrafish cardiac development requires a conserved secondary heart field. Development 2011, 138, 2389–2398.
  44. Cai, C.L.; Liang, X.; Shi, Y.; Chu, P.H.; Pfaff, S.L.; Chen, J.; Evans, S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev. Cell 2003, 5, 877–889.
  45. Lazic, S.; Scott, I.C. Mef2cb regulates late myocardial cell addition from a second heart field-like population of progenitors in zebrafish. Dev. Biol. 2011, 354, 123–133.
  46. Hu, N.; Sedmera, D.; Yost, H.J.; Clark, E.B. Structure and function of the developing zebrafish heart. Anat. Rec. 2000, 260, 148–157.
  47. Gupta, V.; Poss, K.D. Clonally dominant cardiomyocytes direct heart morphogenesis. Nature 2012, 484, 479–484.
  48. Liu, J.; Bressan, M.; Hassel, D.; Huisken, J.; Staudt, D.; Kikuchi, K.; Poss, K.D.; Mikawa, T.; Stainier, D.Y.R. A dual role for ErbB2 signaling in cardiac trabeculation. Development 2010, 137, 3867–3875.
  49. Foglia, M.J.; Cao, J.; Tornini, V.A.; Poss, K.D. Multicolor mapping of the cardiomyocyte proliferation dynamics that construct the atrium. Development 2016, 143, 1688–1696.
  50. Thomas, N.A.; Koudijs, M.; van Eeden, F.J.M.; Joyner, A.L.; Yelon, D. Hedgehog signaling plays a cell-autonomous role in maximizing cardiac developmental potential. Development 2008, 135, 3789–3799.
  51. Dohn, T.E.; Waxman, J.S. Distinct phases of Wnt/β-catenin signaling direct cardiomyocyte formation in zebrafish. Dev. Biol. 2012, 361, 364–376.
  52. Ueno, S.; Weidinger, G.; Osugi, T.; Kohn, A.D.; Golob, J.L.; Pabon, L.; Reinecke, H.; Moon, R.T.; Murry, C.E. Biphasic role for Wnt/β-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 9685–9690.
  53. Deshwar, A.R.; Chng, S.C.; Ho, L.; Reversade, B.; Scott, I.C. The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development. Elife 2016, 5.
  54. Scott, I.C.; Masri, B.; D’Amico, L.A.; Jin, S.W.; Jungblut, B.; Wehman, A.M.; Baier, H.; Audigier, Y.; Stainier, D.Y.R. The G Protein-Coupled receptor agtrl1b regulates early development of myocardial progenitors. Dev. Cell 2007, 12, 403–413.
  55. Stainier, D.Y.R.; Fishman, M.C. Patterning the zebrafish heart tube: Acquisition of anteroposterior polarity. Dev. Biol. 1992, 153, 91–101.
  56. Hochgreb, T.; Linhares, V.L.; Menezes, D.C.; Sampaio, A.C.; Yan, C.Y.I.; Cardoso, W.V.; Rosenthal, N.; Xavier-Neto, J. A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field. Development 2003, 130, 5363–5374.
  57. Keegan, B.R.; Feldman, J.L.; Begemann, G.; Ingham, P.W.; Yelon, D. Retinoic acid signaling restricts the cardiac progenitor pool. Science 2005, 307, 247–249.
  58. Waxman, J.S.; Keegan, B.R.; Roberts, R.W.; Poss, K.D.; Yelon, D. Hoxb5b Acts Downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Dev. Cell 2008, 15, 923–934.
  59. Waxman, J.S.; Yelon, D. Increased hox activity mimics the teratogenic effects of excess retinoic acid signaling. Dev. Dyn. 2009, 238, 1207–1213.
  60. D’Aniello, E.; Rydeen, A.B.; Anderson, J.L.; Mandal, A.; Waxman, J.S. Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid. PLoS Genet. 2013, 9, 1003689.
  61. Marques, S.R.; Lee, Y.; Poss, K.D.; Yelon, D. Reiterative roles for FGF signaling in the establishment of size and proportion of the zebrafish heart. Dev. Biol. 2008, 321, 397–406.
  62. Marques, S.R.; Yelon, D. Differential requirement for BMP signaling in atrial and ventricular lineages establishes cardiac chamber proportionality. Dev. Biol. 2009, 328, 472–482.
  63. De Pater, E.; Ciampricotti, M.; Priller, F.; Veerkamp, J.; Strate, I.; Smith, K.; Lagendijk, A.K.; Schilling, T.F.; Herzog, W.; Abdelilah-Seyfried, S.; et al. Bmp signaling exerts opposite effects on cardiac differentiation. Circ. Res. 2012, 110, 578–587.
  64. Reischauer, S.; Stone, O.A.; Villasenor, A.; Chi, N.; Jin, S.W.; Martin, M.; Lee, M.T.; Fukuda, N.; Marass, M.; Witty, A.; et al. Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification. Nature 2016, 535, 294–298.
  65. Schoenebeck, J.J.; Keegan, B.R.; Yelon, D. Vessel and blood specification override cardiac potential in anterior mesoderm. Dev. Cell 2007, 13, 254–267.
  66. Zhou, Q.; Li, L.; Zhao, B.; Guan, K.-L. The hippo pathway in heart development, regeneration, and diseases. Circ. Res. 2015, 116, 1431–1447.
  67. Fukui, H.; Miyazaki, T.; Chow, R.W.Y.; Ishikawa, H.; Nakajima, H.; Vermot, J.; Mochizuki, N. Hippo signaling determines the number of venous pole cells that originate from the anterior lateral plate mesoderm in zebrafish. Elife 2018, 7.
  68. Witzel, H.R.; Cheedipudi, S.; Gao, R.; Stainier, D.Y.R.; Dobreva, G.D. Isl2b regulates anterior second heart field development in zebrafish. Sci. Rep. 2017, 7, 1–9.
  69. Pereira, F.A.; Yuhong, Q.; Zhou, G.; Tsai, M.J.; Tsai, S.Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 1999, 13, 1037–1049.
  70. Duong, T.B.; Ravisankar, P.; Song, Y.C.; Gafranek, J.T.; Rydeen, A.B.; Dohn, T.E.; Barske, L.A.; Crump, J.G.; Waxman, J.S. Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling-independent and -dependent mechanisms. Dev. Biol. 2018, 434, 7–14.
  71. Barth, A.S.; Merk, S.; Arnoldi, E.; Zwermann, L.; Kloos, P.; Gebauer, M.; Steinmeyer, K.; Bleich, M.; Kääb, S.; Pfeufer, A.; et al. Functional profiling of human atrial and ventricular gene expression. Pflugers Arch. Eur. J. Physiol. 2005, 450, 201–208.
  72. Xin, M.; Small, E.M.; Van Rooij, E.; Qi, X.; Richardson, J.A.; Srivastava, D.; Nakagawa, O.; Olson, E.N. Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function. Proc. Natl. Acad. Sci. USA 2007, 104, 7975–7980.
  73. Targoff, K.L.; Colombo, S.; George, V.; Schell, T.; Kim, S.H.; Solnica-Krezel, L.; Yelon, D. Nkx genes are essential for maintenance of ventricular identity. Development 2013, 140, 4203–4213.
  74. Pradhan, A.; Zeng, X.X.I.; Sidhwani, P.; Marques, S.R.; George, V.; Targoff, K.L.; Chi, N.C.; Yelon, D. FGF signaling enforces cardiac chamber identity in the developing ventricle. Development 2017, 144, 1328–1338.
  75. George, V.; Colombo, S.; Targoff, K.L. An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood. Dev. Biol. 2015, 400, 10–22.
  76. Reifers, F.; Walsh, E.C.; Léger, S.; Stainier, D.Y.R.; Brand, M. Induction and differentiation of the zebrafish heart requires fibroblast growth factor 8 (fgf8/acerebellar). Development 2000, 127, 225–235.
  77. Zhang, R.; Han, P.; Yang, H.; Ouyang, K.; Lee, D.; Lin, Y.F.; Ocorr, K.; Kang, G.; Chen, J.; Stainier, D.Y.R.; et al. In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature 2013, 498, 497–501.
  78. Wu, S.P.; Cheng, C.M.; Lanz, R.B.; Wang, T.; Respress, J.L.; Ather, S.; Chen, W.; Tsai, S.J.; Wehrens, X.H.T.; Tsai, M.J.; et al. Atrial identity is determined by a COUP-TFII regulatory network. Dev. Cell 2013, 25, 417–426.
  79. Arrenberg, A.B.; Stainier, Y.R.; Baier, H.; Huisken, J. Optogenetic control of cardiac function. Source Sci. 2010, 330, 971–974.
  80. Van Weerd, J.H.; Christoffels, V.M. The formation and function of the cardiac conduction system. Development 2016, 143, 197–210.
  81. Burkhard, S.; van Eif, V.; Garric, L.; Christoffels, V.; Bakkers, J. On the evolution of the cardiac pacemaker. J. Cardiovasc. Dev. Dis. 2017, 4, 4.
  82. Wiese, C.; Grieskamp, T.; Airik, R.; Mommersteeg, M.T.M.; Gardiwal, A.; De Gier-De Vries, C.; Schuster-Gossler, K.; Moorman, A.F.M.; Kispert, A.; Christoffels, V.M. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ. Res. 2009, 104, 388–397.
  83. Hoogaars, W.M.H.; Engel, A.; Brons, J.F.; Verkerk, A.O.; De Lange, F.J.; Wong, L.Y.E.; Bakker, M.L.; Clout, D.E.; Wakker, V.; Barnett, P.; et al. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev. 2007, 21, 1098–1112.
  84. Espinoza-Lewis, R.A.; Liu, H.; Sun, C.; Chen, C.; Jiao, K.; Chen, Y.P. Ectopic expression of Nkx2.5 suppresses the formation of the sinoatrial node in mice. Dev. Biol. 2011, 356, 359–369.
  85. Nakashima, Y.; Yanez, D.A.; Touma, M.; Nakano, H.; Jaroszewicz, A.; Jordan, M.C.; Pellegrini, M.; Roos, K.P.; Nakano, A. Nkx2-5 suppresses the proliferation of atrial myocytes and conduction system. Circ. Res. 2014, 114, 1103–1113.
  86. Mommersteeg, M.T.M.; Hoogaars, W.M.H.; Prall, O.W.J.; De Gier-De Vries, C.; Wiese, C.; Clout, D.E.W.; Papaioannou, V.E.; Brown, N.A.; Harvey, R.P.; Moorman, A.F.M.; et al. Molecular pathway for the localized formation of the sinoatrial node. Circ. Res. 2007, 100, 354–362.
  87. Sun, Y.; Liang, X.; Najafi, N.; Cass, M.; Lin, L.; Cai, C.L.; Chen, J.; Evans, S.M. Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev. Biol. 2007, 304, 286–296.
  88. Weinberger, F.; Mehrkens, D.; Friedrich, F.W.; Stubbendorff, M.; Hua, X.; Müller, J.C.; Schrepfer, S.; Evans, S.M.; Carrier, L.; Eschenhagen, T. Localization of islet-1-positive cells in the healthy and infarcted adult murine heart. Circ. Res. 2012, 110, 1303–1310.
  89. Blaschke, R.J.; Hahurij, N.D.; Kuijper, S.; Just, S.; Wisse, L.J.; Deissler, K.; Maxelon, T.; Anastassiadis, K.; Spitzer, J.; Hardt, S.E.; et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation 2007, 115, 1830–1838.
  90. Liang, X.; Zhang, Q.; Cattaneo, P.; Zhuang, S.; Gong, X.; Spann, N.J.; Jiang, C.; Cao, X.; Zhao, X.; Zhang, X.; et al. Transcription factor ISL1 is essential for pacemaker development and function. J. Clin. Investig. 2015, 125, 3256–3268.
  91. Espinoza-Lewis, R.A.; Yu, L.; He, F.; Liu, H.; Tang, R.; Shi, J.; Sun, X.; Martin, J.F.; Wang, D.; Yang, J.; et al. Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev. Biol. 2009, 327, 376–385.
  92. Liu, H.; Chen, C.H.; Espinoza-Lewis, R.A.; Jiao, Z.; Sheu, I.; Hu, X.; Lin, M.; Zhang, Y.; Chen, Y.P. Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function. J. Biol. Chem. 2011, 286, 17029–17038.
  93. Burkhard, S.B.; Bakkers, J. Spatially resolved RNA-sequencing of the embryonic heart identifies a role for Wnt/β-catenin signaling in autonomic control of heart rate. Elife 2018, 7.
  94. Hoffmann, S.; Berger, I.M.; Glaser, A.; Bacon, C.; Li, L.; Gretz, N.; Steinbeisser, H.; Rottbauer, W.; Just, S.; Rappold, G. Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia. Basic Res. Cardiol. 2013, 108, 339.
  95. Colombo, S.; De Sena-Tomaś, C.; George, V.; Werdich, A.A.; Kapur, S.; Macrae, C.A.; Targoff, K.L. Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through isl1 repression. Development 2018, 145.
  96. Bressan, M.; Liu, G.; Mikawa, T. Early mesodermal cues assign avian cardiac pacemaker fate potential in a tertiary heart field. Science 2013, 340, 744–748.
  97. Mommersteeg, M.T.M.; Domínguez, J.N.; Wiese, C.; Norden, J.; De Gier-De Vries, C.; Burch, J.B.E.; Kispert, A.; Brown, N.A.; Moorman, A.F.M.; Christoffels, V.M. The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc. Res. 2010, 87, 92–101.
  98. Ren, J.; Han, P.; Ma, X.; Farah, E.N.; Bloomekatz, J.; Zeng, X.X.I.; Zhang, R.; Swim, M.M.; Witty, A.D.; Knight, H.G.; et al. Canonical Wnt5b Signaling Directs Outlying Nkx2.5+ Mesoderm into Pacemaker Cardiomyocytes. Dev. Cell 2019, 50, 729–743.
  99. Liang, W.; Han, P.; Kim, E.H.; Mak, J.; Zhang, R.; Torrente, A.G.; Goldhaber, J.I.; Marbán, E.; Cho, H.C. Canonical Wnt signaling promotes pacemaker cell specification of cardiac mesodermal cells derived from mouse and human embryonic stem cells. Stem Cells 2020, 38, 352–368.
More