Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Organogenesis

Patterning the vertebrate heart

Nature Reviews Genetics volume 3, pages 544–556 (2002)Cite this article

Key Points

  • The vertebrate heart is a highly modified muscular vessel, which is composed of numerous cell lineages.

  • Heart patterning is a complex and spatially and temporally dynamic process.

  • The cardiac precursor zone in the embryo gives rise to myocardial and endocardial cells of the forming heart tube, as well as to pericardial cells and to a distinct precursor population called the secondary heart field.

  • Secondary heart field cells give rise to the outflow tract and possibly to the right ventricle of the heart after the primary heart tube has formed.

  • The heart precursor zone is shaped by positive (BMP, Fgf and anti-Wnt) and negative (Wnt and anti-BMP) signals from surrounding tissues.

  • Ventral migration of heart precursor cells to form a heart tube requires transcription factors Mesp1 and 2, secreted factors Fgf4 and Fgf8, signalling through the sphingosine-1-phosphate receptor and the graded distribution of the extracellular-matrix component fibronectin.

  • Formation of the atrial component of the heart and its venous tributaries requires retinoic-acid signalling.

  • Chamber muscle is formed on the outer surface of the primary heart tube in response to patterning information, and this process requires an endocardial signal from neuregulin 1, myocardial transcription factors Nkx2-5, Fast2 and Tbx2/5, and complex matrix components.

  • The embryonic left–right asymmetry pathway specifies asymmetric morphogenesis of the atria and its venous components, although whether it also defines the direction of ventricular bending remains contentious.

Abstract

The mammalian heart is crafted from a few progenitor cells that are subject to rapidly changing sets of instructions from their environment and from within. These instructions cause them to migrate, expand and diversify in lineage, and acquire form and function. Molecular information from various model systems, combined with increasingly detailed morphogenetic data, has provided insights into some of these key events. Many congenital heart abnormalities might arise from defects in the early stages of heart development, therefore it is important to understand the molecular pathways that underlie the lineage specification and patterning processes that shape this organ.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The cardiac crescent.
Figure 2: Positive and negative signals that shape the cardiac progenitor zone.
Figure 3: Primary and secondary heart fields.
Figure 4: Regional expression of the GATA6–LacZ transgene in lateral aspects of the cardiac field.
Figure 5: Role of retinoic acid in heart development.
Figure 6: Left–right asymmetry pathways in the heart.

Similar content being viewed by others

References

  1. Redkar, A., Mongomery, M. & Litvin, J. Fate map of early avian cardiac progenitor cells. Development 128, 2269–2279 (2001).

    CAS  PubMed  Google Scholar 

  2. Markwald, R. R. in Developmental Mechanisms of Heart Disease (eds Clark, E. B., Markwald, R. R. & Takao, A.) 3–27 (Futura Publishing Co., Armonk, New York, 1995).

    Google Scholar 

  3. Tam, P. L. & Schoenwolf, G. C. in Heart Development (eds Harvey, R. P. & Rosenthal, N.) 3–18 (Academic, San Diego, California, 1999).

    Book  Google Scholar 

  4. Garcia-Martinez, V. & Schoenwolf, G. C. Primitive-streak origin of the cardiovascular system in avian embryos. Dev. Biol. 159, 706–719 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Kinder, S. J. et al. The organiser of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development 128, 3623–3634 (2001).

    CAS  PubMed  Google Scholar 

  6. Thomas, P. & Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Schneider, V. A. & Mercola, M. Spatially distinct head and heart inducers within the Xenopus organiser region. Curr. Biol. 9, 800–809 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Beddington, R. S. P. & Robertson, E. J. Axis development and early asymmetry in mammals. Cell 96, 195–209 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Perea-Gomez, A., Rhinn, M. & Ang, S.-L. Role of the anterior visceral endoderm in restricting posterior signals in the mouse embryo. Int. J. Dev. Biol. 45, 311–320 (2001).

    CAS  PubMed  Google Scholar 

  10. Niehrs, C., Kazanskaya, O., Wu, W. & Glinka, A. Dickkopf1 and the Spemann–Mangold head organiser. Int. J. Dev. Biol. 45, 237–240 (2001).

    CAS  PubMed  Google Scholar 

  11. Marvin, M. J., Di Rocco, G., Gardiner, A., Bush, S. M. & Lassar, A. B. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev. 15, 316–327 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schneider, V. A. & Mercola, M. Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev. 15, 304–325 (2001).This paper and reference 11 were the first to describe that heart formation requires active BMP signalling and a repression of Wnt signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nascone, N. & Mercola, M. Endoderm and cardiogenesis: new insights. Trends Cardiovasc. Med. 6, 211–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Schultheiss, T. M., Burch, J. B. E. & Lassar, A. B. A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev. 11, 451–462 (1997).The first paper to show that BMPs have a role in the formation of heart lineages.

    Article  CAS  PubMed  Google Scholar 

  15. Yamagishi, T. et al. Expression of bone morphogenetic protein-5 gene during chick heart development: possible roles in valvuloseptal endocardial cushion formation. Anat. Rec. 264, 313–316 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Solloway, M. J. & Robertson, E. J. Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy with the 60A subgroup. Development 126, 1753–1768 (1999).

    CAS  PubMed  Google Scholar 

  17. Andree, B., Duprez, D., Vorbusch, B., Arnold, H.-H. & Brand, T. BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos. Mech. Dev. 70, 119–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Schlange, T., Andree, B., Arnold, H.-H. & Brand, T. BMP2 is required for early heart development during a distinct time period. Mech. Dev. 91, 259–270 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Ladd, A. N., Yatskievych, T. A. & Antin, P. B. Regulation of avian cardiac myogenesis by activin/TGFβ and bone morphogenetic proteins. Dev. Biol. 204, 407–419 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Shi, Y., Katsev, S., Cai, C. & Evans, S. BMP signaling is required for heart formation in vertebrates. Dev. Biol. 224, 226–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, H. & Bradley, A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977–2986 (1996).

    CAS  PubMed  Google Scholar 

  22. Monzen, K. et al. Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4. Mol. Cell. Biol. 19, 7096–7105 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kishimoto, Y., Lee, K.-H., Zon, L., Hammerschmidt, M. & Schulte-Merker, S. The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124, 4457–4466 (1997).

    CAS  PubMed  Google Scholar 

  24. Schwartz, R. J. & Olson, E. N. Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. Development 126, 4187–4192 (1999).

    CAS  PubMed  Google Scholar 

  25. Sparrow, D. B. et al. Regulation of tinman homologues in Xenopus embryos. Dev. Biol. 227, 65–79 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Liberatore, C. M., Searcy-Schrick, R. D., Vincent, E. B. & Yutzey, K. E. Nkx-2.5 gene induction in mice is mediated by a Smad consensus regulatory region. Dev. Biol. 244, 243–256 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Lien, C.-L., McAnally, J., Richardson, J. A. & Olson, E. N. Cardiac-specific activity of an Nkx2-5 enhancer requires an evolutionarily conserved smad binding site. Dev. Biol. 244, 257–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Monzen, K. et al. Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. J. Cell Biol. 153, 687–698 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alsan, B. H. & Schultheiss, T. M. Regulation of avian cardiogenesis by Fgf8 signaling. Development 129, 1935–1943 (2002).This paper shows that Fibroblast growth factor 8 is required for inducing cardiogenesis.

    CAS  PubMed  Google Scholar 

  30. Tzahor, E. & Lassar, A. B. Wnt signals from the neural tube block ectopic cardiogenesis. Genes Dev. 15, 255–260 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goldstein, A. M. & Fishman, M. C. Notochord regulates cardiac lineages in zebrafish development. Dev. Biol. 201, 247–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Black, B. L. & Olson, E. N. in Heart Development (eds Harvey, R. P. & Rosenthal, N.) 131–142 (Academic, San Diego, California, 1999).

    Book  Google Scholar 

  33. Bruneau, B. G. et al. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt–Oram syndrome. Dev. Biol. 211, 100–108 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Harvey, R. P. NK-2 homeobox genes and heart development. Dev. Biol. 178, 203–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Meins, M., Henderson, D. J., Bhattasharya, S. S. & Sowden, J. C. Characterisation of the human TBX20 gene, a new member of the T-box gene family closely related to the Drosophila H15 gene. Genomics 67, 317–332 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Srivastava, D., Cserjesi, P. & Olson, E. N. A subclass of bHLH proteins required for cardiac morphogenesis. Science 270, 1995–1999 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Molkentin, J. D. The zinc finger-containing transcription factors GATA-4, -5, and -6. J. Biol. Chem. 275, 38949–38952 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Harvey, R. P. in Mouse Development: Patterning, Morphogenesis and Organogenesis (eds Rossant, J. & Tam, P. L.) 331–370 (Academic, San Diego, California, 2002).

    Book  Google Scholar 

  39. Auda-Boucher, G. et al. Staging of commitment of murine cardiac cell progenitors. Dev. Biol. 225, 214–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Reiter, J. F., Verkade, H. & Stainier, D. Y. Bmp2b and Oep promote early myocardial differentiation through their regulation of gata5. Dev. Biol. 234, 330–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Eisenberg, C. A. & Eisenberg, L. M. WNT11 promotes cardiac tissue formation of early mesoderm. Dev. Dyn. 216, 45–58 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Zhang, X. M., Ramalho-Santos, M. & McMahon, A. P. Smoothened mutants reveal redundant roles for Shh and Ihh signalling including regulation of L/R asymmetry by the mouse node. Cell 105, 781–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Dyer, M. A., Farrington, S. M., Mohn, D., Munday, J. R. & Baron, M. H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128, 1717–1730 (2001).

    CAS  PubMed  Google Scholar 

  44. Mjaatvedt, C. H. et al. in Heart Development (eds Harvey, R. P. & Rosenthal, N.) 159–177 (Academic, San Diego, California, 1999).

    Book  Google Scholar 

  45. Mikawa, T. in Heart Development (eds Harvey, R. P. & Rosenthal, N.) 19–33 (Academic, San Diego, California, 1999).

    Book  Google Scholar 

  46. Linask, K. K. & Lash, J. W. Early heart development: dynamics of endocardial cell sorting suggests a common origin with cardiomyocytes. Dev. Dyn. 195, 62–66 (1993).

    Article  Google Scholar 

  47. Eisenberg, L. M. & Markwald, R. R. Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ. Res. 77, 1–6 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Stanley, E. G. et al. Efficient Cre-mediated deletion in cardiac progenitor cells conferred by a 3′UTR–Cre allele of the homeobox gene Nkx2-5. Int. J. Dev. Biol. 46, 431–439 (2002).

    CAS  PubMed  Google Scholar 

  49. Lints, T. J., Parsons, L. M., Hartley, L., Lyons, I. & Harvey, R. P. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119, 419–431 (1993).

    CAS  PubMed  Google Scholar 

  50. Coffin, J. D. & Poole, T. J. Endothelial cell origin and migration in embryonic heart and cranial blood vessel development. Anat. Rec. 231, 383–395 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Kitajima, S., Takagi, A., Inoue, T. & Saga, Y. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127, 3215–3226 (2000).

    CAS  PubMed  Google Scholar 

  52. Sun, X., Meyers, E. N., Lewandoski, M. & Martin, G. R. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 13, 1834–1846 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ciruna, B. & Rossant, J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev. Cell 1, 37–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Beiman, M., Shilo, B.-Z. & Volk, T. Heartless, a Drosophila FGF receptor homologue, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev. 10, 2993–3002 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Gisselbrecht, S., Skeath, J. B., Doe, C. Q. & Michelson, A. M. heartless encodes a fibroblastic growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. Genes Dev. 10, 3003–3017 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Zelzer, E. & Shilo, B. Z. Cell fate choices in Drosophila tracheal morphogenesis. Bioessays 22, 219–226 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. DeHaan, R. L. Organisation of the cardiogenic plate in the early chick embryo. Acta Embryol. Morphol. Exp. 6, 26–38 (1963).

    Google Scholar 

  58. Linask, K. K. & Lash, J. W. in Living Morphogenesis of the Heart (eds de la Cruz, M. V. & Markwald, R. R.) 1–41 (Birkhauser, Boston, Massachusetts, 1998).

    Book  Google Scholar 

  59. George, E. L., Baldwin, H. S. & Hynes, R. O. Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 90, 3073–3081 (1997).

    CAS  PubMed  Google Scholar 

  60. Stainier, D. Y. R. Zebrafish genetics and vertebrate heart formation. Nature Rev. Genet. 2, 39–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Narita, N., Bielinska, M. & Wilson, D. B. Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse. Dev. Biol. 189, 270–274 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Parmacek, M. S. & Leiden, J. M. in Heart Development (eds Harvey, R. P. & Rosenthal, N.) 291–306 (Academic, San Diego, California, 1999).

    Book  Google Scholar 

  63. Reiter, J. F. et al. Gata5 is required for development of the heart and endoderm in zebrafish. Genes Dev. 13, 2983–2995 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Crispino, J. D. et al. Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev. 15, 839–844 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kupperman, E., An, S., Osborne, N., Waldron, S. & Stainier, D. Y. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate development. Nature 406, 192–195 (2000).Describes the identification of a zebrafish mutation in a sphingolipid receptor gene that is necessary for the migration of heart progenitors.

    Article  CAS  PubMed  Google Scholar 

  66. Levade, T. et al. Sphingolipid mediators in cardiovascular cell biology and pathology. Circ. Res. 89, 957–968 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Jacobson, A. G. & Sater, A. K. Features of embryonic induction. Development 104, 341–359 (1988).

    CAS  PubMed  Google Scholar 

  68. Raffin, M. et al. Subdivision of the cardiac Nkx2.5 expression domain into myogenic and nonmyogenic compartments. Dev. Biol. 218, 326–340 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Rones, M. S., McLaughlin, K. A., Raffin, M. & Mercola, M. Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis. Development 127, 3865–3876 (2000).

    CAS  PubMed  Google Scholar 

  70. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signalling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Ehrman, L. A. & Yutzey, K. Lack of regulation in the heart forming region of avian embryos. Dev. Biol. 207, 163–175 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Mjaatvedt, C. H. et al. The outflow tract of the heart is recruited from a novel heart-forming field. Dev. Biol. 238, 97–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Waldo, K. L. et al. Conotruncal myocardium arises from a secondary heart field. Development 128, 3179–3188 (2001).

    CAS  PubMed  Google Scholar 

  74. Kelly, R. G., Brown, N. A. & Buckingham, M. E. The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev. Cell 1, 435–440 (2001).References 72–74 report the discovery of a secondary heart field that contributes cells to the outflow tract and possibly to the right ventricle during heart tube formation.

    Article  CAS  PubMed  Google Scholar 

  75. De la Cruz, M. V., Sanchez-Gomez, C., Arteaga, M. M. & Arguello, C. Experimental study of the development of the truncus and conus in the chick embryo. J. Anat. 123, 661–686 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lin, Q., Schwarz, J., Bucana, C. & Olson, E. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276, 1404–1407 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lyons, I. et al. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeobox gene Nkx2-5. Genes Dev. 9, 1654–1666 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Srivastava, D., Thomas, T., Lin, Q., Brown, D. & Olson, E. N. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nature Genet. 16, 154–160 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Clark, E. B. Pathogenetic mechanisms of congenital cardiovascular malformations revisited. Semin. Perinatol. 20, 465–472 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Firulli, A. B. & Olson, E. N. Modular regulation of muscle gene transcription: a mechanism for muscle cell diversity. Trends Genet. 13, 364–369 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Davis, D. L. et al. A GATA-6 gene heart-region-specific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system. Mech. Dev. 108, 105–119 (2001).Reports the expression pattern of a mouse lacZ transgene that reveals the early allocation of heart field cells to the cardiac conduction system.

    Article  CAS  PubMed  Google Scholar 

  82. Webb, S., Brown, N. A. & Anderson, R. H. Formation of the atrioventricular septal structures in the normal mouse. Circ. Res. 82, 645–656 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Satin, J., Fujii, S. & DeHaan, R. L. Development of cardiac beat rate in early chick embryos is regulated by regional cues. Dev. Biol. 129, 103–113 (1988).

    Article  CAS  PubMed  Google Scholar 

  84. Moorman, A. F. M. et al. Presence of functional sarcoplasmic reticulum in the developing heart and its confinement to chamber myocardium. Dev. Biol. 223, 279–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Yutzey, K. E., Rhee, J. T. & Bader, D. Expression of the atrial-specific myosin heavy chain AMHC-1 and the establishment of anteroposterior polarity in the developing chicken heart. Development 120, 871–883 (1994).

    CAS  PubMed  Google Scholar 

  86. Zile, M. H. Vitamin A and embryonic development: an overview. J. Nutr. 128, 455S–458S (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Kastner, P. et al. Vitamin A deficiency and mutations of RXRα, RXRβ and RARα lead to early differentiation of embryonic ventricular cardiomyocytes. Development 124, 4749–4758 (1997).

    CAS  PubMed  Google Scholar 

  88. Rosenthal, N. & Xavier-Neto, J. From the bottom of the heart: anteroposterior decisions in cardiac muscle differentiation. Curr. Opin. Cell Biol. 12, 742–746 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Xavier-Neto, J. et al. A retinoic acid-inducible transgenic marker of sino-atrial development in the mouse heart. Development 126, 2677–2687 (1999).

    CAS  PubMed  Google Scholar 

  90. Moss, J. B. et al. Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Dev. Biol. 199, 55–71 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Kostetskii, I. et al. Retinoid signalling required for normal heart development regulates GATA-4 in a pathway distinct from cardiomyocyte differentiation. Dev. Biol. 206, 206–218 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Chazaud, C., Chambon, P. & Dolle, P. Retinoic acid is required in the mouse embryo for left–right asymmetry determination and heart morphogenesis. Development 126, 2589–2596 (1999).

    CAS  PubMed  Google Scholar 

  93. Niederreither, K. et al. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 128, 1019–1031 (2001).Provides genetic proof that retinoic acid is required for patterning the heart tube.

    CAS  PubMed  Google Scholar 

  94. Bruneau, B. G. et al. A murine model of Holt–Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106, 709–721 (2001).Describes the charaterization of the Tbx5 -knockout mouse, which is a model of the human Holt–Oram syndrome.

    Article  CAS  PubMed  Google Scholar 

  95. Christoffels, V. M. et al. Chamber formation and morphogenesis in the developing mammalian heart. Dev. Biol. 223, 266–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Liberatore, C. M., Searcy-Schrick, R. D. & Yutzey, K. E. Ventricular expression of tbx5 inhibits normal heart chamber development. Dev. Biol. 223, 169–180 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Markwald, R. R., Truck, T. & Moreno-Rodriguez, R. in Living Morphogenesis of the Heart (eds de la Cruz, M. & Markwald, R. R.) 43–84 (Birkhauser, Berlin, 1998).

    Book  Google Scholar 

  98. Nakagawa, O., Nakagawa, M., Richardson, J. A., Olson, E. N. & Srivastava, D. HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev. Biol. 216, 72–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Leimeister, C., Externbrink, A., Klamt, B. & Gessler, M. Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis. Mech. Dev. 85, 173–177 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Chin, M. T. et al. Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. J. Biol. Chem. 275, 6381–6387 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Nakagawa, O. et al. Members of the HRT family of basic helix–loop–helix proteins act as transcriptional repressors downstream of Notch signalling. Proc. Natl Acad. Sci. USA 97, 13655–13660 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kobubo, H., Lun, Y. & Johnson, R. L. Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split. Biochem. Biophys. Res. Commun. 260, 459–465 (1999).

    Article  Google Scholar 

  103. Leimeister, C. et al. Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Dev. Biol. 227, 91–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Firulli, B. A., Hadzic, D. B., McDaid, J. R. & Firulli, A. The basic helix–loop–helix transcription factors dHand and eHand exhibit dimerisation characteristics that suggest complex regulation of function. J. Biol. Chem. 275, 33567–33573 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Bounpheng, M. A., Morrish, T. A., Dodds, S. G. & Christy, B. A. Negative regulation of selected bHLH proteins by eHand. Exp. Cell Res. 257, 320–331 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Yamagishi, H. et al. The combined activities of Nkx2-5 and dHand are essential for cardiac ventricle formation. Dev. Biol. 239, 190–203 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Firulli, A. B., McFadden, D. G., Lin, Q., Srivastava, D. & Olson, E. N. Heart and extra-embryonic mesoderm defects in mouse embryos lacking the bHLH transcription factor Hand1. Nature Genet. 18, 266–270 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Riley, P., Anson-Cartwright, L. & Cross, J. C. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nature Genet. 18, 271–275 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Yelon, D. et al. The bHLH transcription factor Hand2 plays parallel roles in zebrafish heart and pectoral fin development. Development 127, 2573–2582 (2000).

    CAS  PubMed  Google Scholar 

  110. Eldadah, Z. A. et al. Familial tetralogy of Fallot caused by mutation in the jagged1 gene. Hum. Mol. Genet. 10, 163–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Icardo, J. M. & Fernandez-Teran, A. Morphologic study of ventricular trabeculation in the embryonic chick heart. Acta Anat. 130, 264–274 (1987).

    Article  CAS  PubMed  Google Scholar 

  112. Palmer, S. et al. The small muscle-specific protein Csl modifies cell shape and promotes myocyte fusion in an insulin-like growth factor 1-dependent manner. J. Cell Biol. 153, 985–997 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Christoffels, V. M., Keijser, A. G. M., Houweling, A. C., Clout, D. E. W. & Moorman, A. F. M. Patterning the embryonic heart: identification of five mouse Iroquois homeobox genes in the developing heart. Dev. Biol. 224, 263–274 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Gassmann, M. et al. Aberrent neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, K.-F. et al. Requirement for neuregulin receptor ErbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    Article  CAS  PubMed  Google Scholar 

  117. Woldeyesus, M. T. et al. Peripheral nervous system expression defects in erbB2 mutants following rescue of heart development. Genes Dev. 13, 2538–2548 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bourguignon, L. Y. W. et al. Hyaluronan (HA) promotes CD44v3–Vav2 interaction with Grb2-p185HER2 and induces Rac1 and Ras signalling during ovarian tumour cell migration and growth. J. Biol. Chem. 276, 48679–48692 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Camenisch, T. D. et al. Disruption of hyaluronan synthetase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J. Clin. Invest. 106, 349–360 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nebigil, C. G. et al. Serotonin 2B receptor is required for heart development. Proc. Natl Acad. Sci. USA 97, 9508–9513 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Offermanns, S. et al. Embryonic cardiomyocyte hyperplasia and craniofacial defects in Gαq/Gα11-mutant mice. EMBO J. 17, 4304–4312 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hackel, P. O., Zwick, E., Prenzel, N. & Ullrich, A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr. Opin. Cell Biol. 11, 184–189 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Hiroi, Y. et al. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nature Genet. 28, 276–280 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Biben, C. & Harvey, R. P. Homeodomain factor Nkx2-5 controls left–right asymmetric expression of bHLH eHand during murine heart development. Genes Dev. 11, 1357–1369 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Tanaka, M., Chen, Z., Bartunkova, S., Yamasaki, N. & Izumo, S. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes for heart development. Development 126, 1269–1280 (1999).

    CAS  PubMed  Google Scholar 

  126. Biben, C., Palmer, D. A., Elliot, D. A. & Harvey, R. P. in Cold Spring Harbor Symposia on Quantitative Biology Vol. LXIII 395–403 (Cold Spring Harbor Laboratory Press, New York, 1997).

    Google Scholar 

  127. Hoodless, P. A. et al. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15, 1257–1271 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yamamoto, M. et al. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior–posterior patterning and node formation in the mouse. Genes Dev. 15, 1242–1256 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Habets, P. E. M. H. et al. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 16, 1234–1246 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bowers, P. N., Brueckner, M. & Yost, H. J. Laterality disturbances. Prog. Pediatr. Cardiol. 6, 53–62 (1996).

    Article  Google Scholar 

  131. Harvey, R. P. Cardiac looping: an uneasy deal with laterality. Semin. Cell Dev. Biol. 9, 101–108 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Campione, M. et al. Pitx2 expression defines a left cardiac lineage of cell: evidence for atrial and ventricular molecular isomerism. Dev. Biol. 231, 252–264 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. & Tabin, C. A molecular pathway determining left–right asymmetry in chick embryogenesis. Cell 82, 803–814 (1995).This landmark paper provided the first evidence of a molecular pathway for left–right asymmetry in the embryo.

    Article  CAS  PubMed  Google Scholar 

  134. Capdevila, J., Vogan, K. J., Tabin, C. J. & Izpisua Belmonte, J.-C. Mechanisms of left–right determination in vertebrates. Cell 101, 9–21 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  136. Meno, C. et al. Diffusion of nodal signaling activity in the absence of the feedback inhibitor lefty2. Dev. Cell 1, 127–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Logan, M., Pagan-Westphal, S. M., Smith, D. M., Paganessi, L. & Tabin, C. J. The transcription factor Ptx2 mediates situs-specific morphogenesis in response to left–right asymmetric signals. Cell 94, 307–317 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  139. Garcia-Castro, M., Vielmetter, E. & Bronner-Fraser, M. N-cadherin, a cell adhesion molecule involved in establishment of embryonic left–right asymmetry. Science 288, 1047–1051 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Brown, N. A. & Wolpert, L. The development of handedness in left/right asymmetry. Development 109, 1–9 (1990).

    CAS  PubMed  Google Scholar 

  141. Levin, M. & Mercola, M. The compulsion of chirality: towards an understanding of left–right asymmetry. Genes Dev. 12, 763–769 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Patel, K., Isaac, A. & Cooke, J. Nodal signalling and the roles of the transcription factors SnR and Pitx2 in vertebrate left–right asymmetry. Curr. Biol. 9, 609–612 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Prall, O. W., Elliott, D. A. & Harvey, R. P. Developmental paradigms in heart disease: insights from Tinman. Ann. Med. 34, (in the press).

  144. Kocher, A. A. et al. Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nature Med. 7, 430–436 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Leferovich, J. M. et al. Heart regeneration in adult MRL mice. Proc. Natl Acad. Sci. USA 98, 9830–9835 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Xavier–Neto, J., Shapiro, M. D., Houghton, L. & Rosenthal, N. Sequential programs of retinoic acid synthesis in the myocardial and epicardial layers of the developing avian heart. Dev. Biol. 219, 129–141 (2000).

    Article  PubMed  CAS  Google Scholar 

  148. Yan, Y. T. et al. Conserved requirement for EGF–CFC genes in vertebrate left–right axis formation. Genes Dev. 13, 2527–2537 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank N. Rosenthal for the artwork in the boxes and in figure 3, and N. Groves and C. Biben for help in preparing the manuscript.

Author information

Authors and Affiliations

  1. Victor Chang Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010, New South Wales, Australia

    Richard P. Harvey

Authors
  1. Richard P. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Flybase

Delta

hairy/enhancer of split

Heartless

Hey

Notch

LocusLink

Acvr2b

Aldh1a7

Anf

Atf2

Atp2a2

Bmp4

CD44

Cfc1

Chisel

Cited1

E-cadherin

EGF receptor

Erbb2

Erbb4

Fast2

Fgf4

Fgf8

Fgf10

Fgfr1

Fn1

Fog2

Foxh1a

Gata4

Gata5

Gata6

Gdf1

Gja5

Hand1

Hand2

Has2

Indian hedgehog

Irx1

Irx3

Irx5

Jagged1

Mef2b

Mef2c

Mesp1

Mesp2

neuregulin

Nkx2-5

Nodal

Pitx2

Pln

RALDH2

retinoic acid receptor

retinoid-X receptor

serotonin 2B receptor

Serrate

Smad family

Smo

Snail

T

Tak1

Tbx5

Tbx20

Tgf-β

Wnt

OMIM

cardia bifida

Holt–Oram syndrome

Rieger syndrome

ZFIN

miles apart

Glossary

GASTRULATION

The highly integrated process of cell movements, involving the whole embryo, that leads to formation of the definitive tissue (germ) layers: endoderm, ectoderm and mesoderm.

NEURAL CREST CELLS

A migratory cell population that arises at the lateral extremities of the embryonic neural plate, and which differentiates into various cell types, depending on location. These include endothelial cells, smooth and skeletal muscle cells, bone, adrenal medulla, and cells of the sensory and autonomic nervous systems.

NODE AND ORGANIZER

Analogous structures in mouse/chick and frog embryos, respectively, that represent the main signalling centres in the early period of body plan development, and from which the axial lineages, such as the prechordal plate, notochord and gut endoderm, are derived.

PRIMITIVE STREAK

A morphogenetic furrow formed in embryos and through which cells ingress at gastrulation.

EPIBLAST

Columnar epithelium that lines the amniotic sac floor. This layer generates endoderm and mesoderm by migration of cells through the primitive streak. The remaining cells form ectoderm.

AMNIOTE

A reptile, bird or mammal, in which a membrane, called the amnion, separates the conceptus from its environment.

BRANCHIAL ARCHES

A series of paired segmental structures composed of ectoderm, mesoderm and neural crest cells that are positioned on either side of the developing pharynx. In mammals, the branchial arches contribute to pharyngeal organs and to the connective, skeletal, neural and vascular tissues of the head and neck.

TERATOGENIC

Able to cause birth defects.

METAMERIC

Composed of similar segments (metameres), as in the body plan of segmented animals such as arthropods, and in embryonic structures such as somites and rhombomeres of the hindbrain.

SOMITOGENESIS

The process of progressive formation, during embryogenesis, of metameric mesodermal units (somites) that represent the precursor structures of dermis, skeletal muscles and the axial skeleton.

LATERAL-PLATE MESODERM

The mesoderm that is located in the lateral region of the early somite-stage embryo.

ATRIAL SEPTAL DEFECT

Abnormal development of the atrial septum in humans, which leads to a persistent communication between left and right atria, generally progressing to right heart failure in the middle years of life.

TETRALOGY OF FALLOT

Complex congenital heart abnormality showing ventricular septal defect (hole in the interventricular septum), an aorta that communicates with both left and right ventricles, narrowing of the pulmonary artery and right ventricular hypertrophy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harvey, R. Patterning the vertebrate heart. Nat Rev Genet 3, 544–556 (2002). https://doi.org/10.1038/nrg843

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg843

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing