Molecular Mechanisms of Cardiac Diversification

  • Jeffrey D. Croissant
  • Stacey Carpenter
  • David Bader
Part of the Cardiovascular Molecular Morphogenesis book series (CARDMM)


The development of the functional vertebrate heart has served as an excellent model system to study the molecular, biochemical, and physiologic regulation of cellular diversification. The atria and ventricles of the mature vertebrate heart are composed of unique subsets of cardiomyocytes that are required for variations in chamber function. While this chapter has explored experimental evidence that has led to a better understanding of the initial critical steps involved in atrial and ventricular diversification, many questions are still unresolved. The atrial-ventricular fate of cardiomyocytes appears to be determined by cellular position within the cardiogenic field and affected by retinoic acid signaling. How retinoic acid and other extracelluar signaling molecules regulate these cellular decisions is not clear. Many chamber-specific molecular and biochemical markers have been isolated. However, additional chamber-specific genes need to be identified to ascertain functional variations between atrial and ventricular myocytes.


Retinoic Acid Myosin Heavy Chain Ventricular Chamber Heart Tube Retinoic Acid Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bao, Z.Z., Bruneau, B.G., Seidman, J.G., Seidman, C.E., and Cepko, C.L. (1999). Regulation of chamber-specific gene expression in the developing heart by Irx4. Science 283:1161–1164.PubMedCrossRefGoogle Scholar
  2. Barany, M. (1967). ATPase activity of myosin correlated with speed of muscle shortening. J Gen Physiol 50(suppl):197–218.PubMedCrossRefGoogle Scholar
  3. Bisaha, J.G., and Bader, D. (1991). Identification and characterization of a ventricular-specific avian myosin heavy chain, VMHC1: expression in differentiating cardiac and skeletal muscle. Dey Biol 148:355–364.CrossRefGoogle Scholar
  4. Carraway, K.L. 3rd, and Burden, S.J. (1995). Neuregulins and their receptors. Curr Opin Neurobiol 5:606–612.PubMedCrossRefGoogle Scholar
  5. Conlon, R.A. (1995). Retinoic acid and pattern formation in vertebrates. Trends Genet 11:314–329.PubMedCrossRefGoogle Scholar
  6. DeHaan, R.L. (1960). Morphogenesis of the vertebrate heart. In: DeHaan, R.L., and Upspring, H., eds. Organogenesis. Holt, Rinhart, and Winston, New York, pp. 377–419.Google Scholar
  7. Dyson, E., Sucov, H.M., Kubalak, S.W., Schmid-Schonbein, G.W., DeLano, F.A., Evans, R.M., Ross, J. Jr, and Chien, K.R. (1995). Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha —/— mice. Proc Natl Acad Sci USA 92:7386–7390.PubMedCrossRefGoogle Scholar
  8. Dersch, H., and Zile, M.H. (1993). Induction of normal cardiovascular development in the vitamin A—deprived quail embryo by natural retinoids. Dey Biol 160:424–433.CrossRefGoogle Scholar
  9. Ehrman, L.A., and Yutzey, K.E. (1999). Lack of regulation in the heart forming region of avian embryos. Dey Biol 207:163–175.CrossRefGoogle Scholar
  10. Evans, D., Miller, J.B., and Stockdale, F.E. (1988). Developmental patterns of expression and coexpression of myosin heavy chains in atria and ventricles of the avian heart. Dey Biol 127:376–383.CrossRefGoogle Scholar
  11. Garcia-Martinez, V., and Schoenwolf, G.C. (1993). Primitive-streak origin of the cardiovascular system in avian embryos. Dey Biol 159:706–719.CrossRefGoogle Scholar
  12. Gassmann, M., Casagranda, F., Orioli, D., Simon H., Lai, C., Klein, R., and Lemke, G. (1995). Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378:390–394.PubMedCrossRefGoogle Scholar
  13. Gonzalez-Sanchez, A., and Bader, D. (1984). Immunochemical analysis of myosin heavy chains in the developing chicken heart. Dev Biol 103:151–158.PubMedCrossRefGoogle Scholar
  14. Gonzalez-Sanchez, A., and Bader, D. (1990). In vitro analysis of cardiac progenitor cell differentiation. Dev Biol 139:197–209.PubMedCrossRefGoogle Scholar
  15. Gruber, P.J., Kubalak, S.W., and Chien, K.R. (1998). Downregulation of atrial markers during cardiac chamber morphogenesis is irreversible in murine embryos. Development 125:4427–4438.PubMedGoogle Scholar
  16. Hamburger, V., and Hamilton, H. (1951). A series of normal stages in the development of the chick embryo. J Morphol 88:49–92.CrossRefGoogle Scholar
  17. Han, Y., Dennis, J.E., Cohen-Gould, L., Bader, D.M., and Fischman, D.A. (1992). Expression of sarcomeric myosin in presumptive myocardium of chicken embryos occurs within six hours of myocyte commitment. Dev Dyn 193:257–265.PubMedCrossRefGoogle Scholar
  18. He, C.Z., and Burch, J.B. (1997). The chicken GATA-6 locus contains multiple control regions that confer distinct patterns of heart region-specific expression in transgenic mouse embryos. J Biol Chem 272:28550–28556.PubMedCrossRefGoogle Scholar
  19. Heine, U.I., Roberts, A.B., Munoz, E.F., Roche, N.S., and Sporn, M.B. (1985). Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo. Virchows Arch [B] 50:135–152.CrossRefGoogle Scholar
  20. Hoh, J.F., McGrath, P.A., and Hale, P.T. (1978). Electrophoretic analysis of multiple forms of rat cardiac myosin: effects of hypophysectomy and thryoxine replacement. J Mol Cell Cardiol 10:1053–1076.PubMedCrossRefGoogle Scholar
  21. Lee, K.F., Simon, H., Chen, H., Bates, B., Hung, M.C., and Hauser, C. (1995). Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398.PubMedCrossRefGoogle Scholar
  22. Lee, K.J., Hickey, R., Zhu, H., and Chien, K.R. (1994). Positive regulatory elements (HF-la and HF-1b) and a novel negative regulatory element (HF-3) mediate ventricular muscle-specific expression of myosin light chain 2-lucifierase fusion genes in transgenic mice. Mol Cell Biol 14:1220–1229.PubMedCrossRefGoogle Scholar
  23. Lee, K.J., Ross, R.S., Rockman, H.A., et al. (1992). Myosin light chain-2 luciferase trans-genic mice reveal distinct regulatory programs for cardiac and skeletal muscle-specific expression of a single contractile protein gene. J Biol Chem 267:15875–15885.PubMedGoogle Scholar
  24. Logan, M., and Mohun, T. (1993). Induction of cardiac muscle differentiation in isolated animal pole explants of Xenopus laevis embryos. Development 118:865–875.PubMedGoogle Scholar
  25. Lompre, A.M., Nadal-Ginard, B., and Mandavi, V. (1984). Expression of the cardiac ventricular alpha-and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem 259:6437–6446.PubMedGoogle Scholar
  26. Lyons, G.E., Schiaffino, S., Sassoon, D., Barton, P., and Buckingham, M. (1990). Developmental regulation of myosin gene expression in mouse cardiac muscle. J Cell Biol 111:2427–2436.PubMedCrossRefGoogle Scholar
  27. Mandavi, V., Izumo, S., and Nadal-Ginard, B. (1987). Develpmental and hormonal regulation of sarcomeric myosin heavy chain gene family. Circ Res 60:804–814.CrossRefGoogle Scholar
  28. Mangelsdorf, D.J., Borgmeyer, U., Heyman, R.A., Zhou, J.Y., Ong, E.S., Oro, A.E., Kakizuka, A., and Evans, R.M. (1992). Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6:329–344.PubMedCrossRefGoogle Scholar
  29. Meyer, D., and Birchmeier, C. (1995). Multiple essential functions of neuregulin in development. Nature 378:386–390.PubMedCrossRefGoogle Scholar
  30. Moss, J.B., Xavier-Neto, J., Shapiro, M.D., et al. (1998). Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Dev Biol 199:55–71.PubMedCrossRefGoogle Scholar
  31. Ng, W.A., Grupp, I.L., Subramaniam, A., and Robbins, J. (1991). Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. Circ Res 68:1742–1750.PubMedCrossRefGoogle Scholar
  32. Nikovits, W., Wang, G.F., Feldman, J.L., et al. (1996). Isolation and characterization of an avian slow myosin heavy chain gene expressed during embryonic skeletal muscle fiber formation. J Biol Chem 271:17047–17056.PubMedCrossRefGoogle Scholar
  33. Oana, S., Machida, S., Hiratsuka, E., Furutani, Y., Momma, K., Takao, A., and Matsuoka, R. (1998). The complete sequence and expression patterns of the atrial myosin heavy chain in the developing chick. Biol Cell 90(9):605–613.PubMedGoogle Scholar
  34. O’Brien, T.X., Lee, K.J., and Chien, K.R. (1993). Positional information of ventricular myosin light chain 2 expression in the primitive murine heart tube. Proc Natl Acad Sci USA 90:5157–5161.PubMedCrossRefGoogle Scholar
  35. Osmond, M.K., Butler, A.J., Voon, F.C., and Bellairs, R. (1991). The effects of retinoic acid on heart formation in the early chick embryo. Development 113:1405–1417.PubMedGoogle Scholar
  36. Patten, B.M. (1929). The Early Embryology of the Chick. Blakiston, Philadelphia.Google Scholar
  37. Rosenquist, G.C. (1985). Migration of precardiac cells from their origin in the epiblast until they form the definitive heart in the chick embryo. In: Ferrans, V.J., Rosenquist, G., and Weinstein, C., eds. Cardiac Morphogenesis. Elsevier, New York, pp. 44–53.Google Scholar
  38. Rosenquist, G.C., and DeHaan, R.L. (1966). Migration of precardiac cells in the chick embryo: a radiographic study. Carnegie Inst Wash Contrib Embryol 38:111–121.Google Scholar
  39. Ross, R.S., Navankasattusas, S., Harvey, R.P., and Chien, K.R. (1996). An HF-la/HF1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. Development 122:1799–1809.PubMedGoogle Scholar
  40. Ruzicka, D.L., and Schwartz, R.J. (1988). Sequential activation of alpha-actin genes during avian cardiogenesis: vascular smooth muscle alpha-actin gene transcripts mark the onset of cardiomyocyte differentiation. J Cell Biol 107:2575–2586.PubMedCrossRefGoogle Scholar
  41. Sater, A.K., and Jacobson, A.G. (1989). The specification of heart mesoderm occurs during gastrulation in Xenopus laevis. Development 105:821–830.Google Scholar
  42. Schwartz, K., Lecarpentier, Y., Martin, J.L., Lompre, A.M., Mercadier, J.J., and Swynghedauw, B. (1981). Myosin isoenzymic distribution correlates with speed of myocardial contraction. J Mol Cell Cardiol 13:1071–1075.PubMedCrossRefGoogle Scholar
  43. Sinha, A.M., Umeda, P.K., Kavinsky, C.J., et al. (1982). Molecular cloning of mRNA sequences for cardiac alpha-and beta-form myosin heavy chains: expression in ventricles of normal, hypothryoid, and thyrotoxic rabbits. Proc Natl Acad Sci USA 79:5847–5851.PubMedCrossRefGoogle Scholar
  44. Smith, S., and Dickman, E.D. (1997). New insights into retinoid signalin in cardiac development and physiology. Trends Cardiovasc Med 7:324–329.PubMedCrossRefGoogle Scholar
  45. Srivastava, D., Thomas, T., Lin, Q., Kirby, M.L., Brown, D., and Olson, E.N. (1997). Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet 16:154–160.PubMedCrossRefGoogle Scholar
  46. Stainier, D.Y., and Fishman, M.C. (1992). Patterning the zebrafish heart tube: aquisition of anteroposterior polarity. Dev Biol 153:91–101.PubMedCrossRefGoogle Scholar
  47. Sucov, H.M., Dyson, E., Gumeringer, C.L., Price, J., Chien, K.R., and Evans, R.M. (1994). RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8:1007–1018.PubMedCrossRefGoogle Scholar
  48. Twal, W., Roze, L., and Zile, M.H. (1995). Anti-retinoic acid monoclonal antibody localizes all-trans-retinoic acid in target cells and blocks normal development in early quail embryo. Dev Biol 168:225–234.PubMedCrossRefGoogle Scholar
  49. Yu, V.C., Delsert, C., Andersen, B., Holloway, J.M., Devary, O.V., Naar, A.M., Kim, S.Y., Boutin, J.M., Glass, C.K., and Rosenfeld, M.G. (1991). RXR beta: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67:1251–1266.PubMedCrossRefGoogle Scholar
  50. Wang, G.F., Nikovits, W., Schleinitz, M., and Stockdale, F.E. (1996). Atrial chamber-specific expression of the slow myosin heavy chain 3 gene in the embryonic heart. J Biol Chem 271:19836–19845.PubMedCrossRefGoogle Scholar
  51. Wang, G.F., Nikovits, W., Schleinitz, M., and Stockdale, F.E. (1998). A positive GATA element and a negative vitamin D receptor-like element control atrial chamber-specific expression of a slow myosin heavy-chain gene during cardiac morphogenesis. Mol Cell Biol 18:6023–6034.PubMedGoogle Scholar
  52. Wilson, J.G., and Warkany, J. (1949). Aortic arch and cardiac anomalies in the offspring of vitamin A deficient rats. Am J Anat 85:113–155.PubMedCrossRefGoogle Scholar
  53. Xavier-Neto, J., Neville, C.M., Shapiro, M.D., et al. (1999). A retinoic acid-inducible trans-genic marker of sino-atrial development in the mouse heart. Development 126:2677–2687.PubMedGoogle Scholar
  54. Yutzey, K., Gannon, M., and Bader, D. (1995). Diversification of cardiomyogenic cell lin-eages in vitro. Dev Biol 170:531–541.PubMedCrossRefGoogle Scholar
  55. Yutzey, K.E., Rhee, J.T., and Bader, D. (1994). Expression of the atrial-specific myosin heavy chain AMHC1 and the establishment of anteroposterior polarity in the developing chicken heart. Development 120:871–883.PubMedGoogle Scholar
  56. Zhang, Y., Shafiq, S.A., and Bader, D. (1986). Detection of a ventricular-specific myosinheavy chain in adult and developing chicken heart. J Cell Biol 102:1480–1484.PubMedCrossRefGoogle Scholar
  57. Zhao, D., McCaffery, P., Ivins, K.J., et al. (1996). Molecular identification of a majorretinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur Journ Biochem 240:15–22.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jeffrey D. Croissant
  • Stacey Carpenter
  • David Bader

There are no affiliations available

Personalised recommendations