Neural Crest and Heart Development

  • Margaret L. Kirby
Part of the Cardiovascular Molecular Morphogenesis book series (CARDMM)


Ablation of cardiac neural crest results in a unique set of morphologic and function changes in cardiovascular development. The most dramatic morphologic changes are seen after the embryonic period is completed and include defective septation of the cardiac outflow tract and mispatterning (or interruption) of the great arteries, which is associated with hypoplastic development of the pharyngeal glands. These phenotypic changes are accompanied by myocardial functional alterations that include defective excitation-contraction coupling from the earliest time of myocardial function, resulting in heart failure. Abnormal ventricular function begins prior to the time when neural crest cells normally reach the heart in an intact embryo. Because the cardiac neural crest cells migrate initially into the pharyngeal region, where they support normal development of the aortic arch arteries, it was initially thought that abnormal development of the aortic (pharyngeal) arch arteries was likely to impact on ventricular development and would thus explain poor myocardial function. The pharyngeal arteries carry all of the cardiac output during a significant portion of early heart development. Loss of neural crest cells that support the endothelial walls of these vascular channels could change the properties of their walls. However, several attempts to document hemodynamic abnormalities in the aortic arch arteries following cardiac neural crest ablation have failed. Coculture of myocardium with endoderm leads to myocardial functional abnormalities similar to those seen in neural crest–ablated embryos. This has led to the hypothesis that an interaction of neural crest cells with pharyngeal endoderm may be required for inhibition or sequestration of a fibroblast growth factor (FGF)-like factor that is deleterious to myocardial development. This recent finding has produced a dramatic revision in classical thinking about the function of cardiac neural crest cells and the interactions that influence normal heart development.


Neural Crest Neural Crest Cell Heart Development Pharyngeal Arch Lateral Plate Mesoderm 
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. Anderson, R.H., Wilkinson, J.L., Arnold, Becker, A.E., and Lubkiewicz, K. (1974). Morphogenesis of bulboventricular malformations. II. Observations on malformed hearts. Br Heart J 36:948.PubMedCrossRefGoogle Scholar
  2. Antin, P.B., Taylor, R.G., and Yatskievych, T. (1994). Precardiac mesoderm is specified during gastrulation in quail. Dey Dyn 200:144–154.CrossRefGoogle Scholar
  3. Antin, P.B., Yatskievych, T., Dominguez, J.L., and Chieffi, P. (1996). Regulation of avian precardiac mesoderm development by insulin and insulin-like growth factors. J Cell Physiol 168:42–50.PubMedCrossRefGoogle Scholar
  4. Bannerman, P.G., and Pleasure, D. (1993). Protein growth factor requirements of rat neural crest cells. J Neurosci Res 36:46–57.PubMedCrossRefGoogle Scholar
  5. Beddington, R.S., and Robertson, E.J. (1998). Anterior patterning in mouse. TIG 14: 277–284.PubMedCrossRefGoogle Scholar
  6. Bockman, D.E., Redmond, M.E., and Kirby, M.L. (1989). Alteration of early vascular development after ablation of cranial neural crest. Anat Rec 225:209–217.PubMedCrossRefGoogle Scholar
  7. Bockman, D.E., Redmond, M.E., Waldo, K., Davis, H., and Kirby, M.L. (1987). Effect of neural crest ablation on development of the heart and arch arteries in the chick. Am J Anat 180:332–341.PubMedCrossRefGoogle Scholar
  8. Chalepakis, G., Stoykova, A., Wijnholds, J., Tremblay, P., and Gruss, P. (1993). Pax: gene regulators in the developing nervous system. J Neurobiol 24:1367–1384.PubMedCrossRefGoogle Scholar
  9. Conway, S.J., Henderson, D.J., Kirby, M.L., Anderson, R.H., and Copp, A.J. (1997). Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc Res 36:163–173.PubMedCrossRefGoogle Scholar
  10. de Ruiter, M.C., Hogers, B., Poelmann, R.E., Vaniperen, L., and Gittenberger-de Groot, A.C. (1991). The development of the vascular system in quail embryos. A combination of microvascular corrosion casts and immunohistochemical identification. Scanning Microsc 5:1081–1090.Google Scholar
  11. Dickinson, M.E., Selleck, M.A.J., McMahon, A.P., and Bronner-Fraser, M. (1995). Dorsal-ization of the neural tube by the non-neural ectoderm. Development 121:2099–2106.PubMedGoogle Scholar
  12. Eisenberg, L.M., and Markwald, R.R. (1995). Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res 77:1–6.PubMedCrossRefGoogle Scholar
  13. Erickson, C.A., and Reedy, M.V. (1998). Neural crest development: the interplay between morphogenesis and cell differentiation. Curr Top Dev Biol 40:177–209.PubMedCrossRefGoogle Scholar
  14. Essex, L.J., Mayor, R., and Sargent, M.G. (1993). Expression of Xenopus snail in mesoderm and prospective neural fold ectoderm. Dev Dyn 198:108–122.PubMedCrossRefGoogle Scholar
  15. Farrell, M.J., Stadt, H.A., Wallis, K.T., Scambler, P., Hixon, R., Wolfe, R.R., Leatherbury, L., and Kirby, M.L. (1999). HIRA, a DiGeorge syndrome candidate gene is required for normal outflow tract septation. Circ Res 84:127–135.PubMedCrossRefGoogle Scholar
  16. Farrell, M.J., Burch, J.L., Rowley, L., Kumiski, D., Stadt, H., Godt, R.E., Creazzo, T.L., and Kirby, M.L. (2000). Pharyngeal endoderm produces a factor that suppresses development of myocardial calcium transients (submitted).Google Scholar
  17. Franz, T., and Kothary, R. (1993). Characterization of the neural crest defect in Splotch (SpIH) mutant mice using a lacZ transgene. Dev Brain Res 72:99–105.CrossRefGoogle Scholar
  18. Gannon, M., and Bader, D. (1995). Initiation of cardiac differentiation occurs in the absence of anterior endoderm. Development 121:2439–2450.PubMedGoogle Scholar
  19. Goulding, M.D., Chalepakis, G., Deutsch, U., Erselius, J.R., and Gruss, P. (1991). Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO J 10:1135–1147.PubMedGoogle Scholar
  20. Han, Y., Dennis, J.E., Cohen-Gould, L., Bader, D.M., and Fischman, D.A. (1992). Expression of sarcomeric myosin in the presumptive myocardium of chicken embryos occurs within six hours of myocyte commitment. Dev Dyn 193:257–265.PubMedCrossRefGoogle Scholar
  21. Haas, T.L., and Duling, B.R. (1997). Morphology favors an endothelial cell pathway for longitudinal conduction within arterioles. Microvasc Res 53:113–120.PubMedCrossRefGoogle Scholar
  22. Hibbs, R.G. (1956). Electron microscopy of developing cardiac muscle in chick embryos. Am J Anat 99:17–52.PubMedCrossRefGoogle Scholar
  23. Hiruma, T., and Hirakow, R. (1985). An ultrastructural topographical study on myofibrillogenesis in the heart of the chick embryo during pulsation onset period. Anat Embryol 172:325–329.PubMedCrossRefGoogle Scholar
  24. Horstadius, S. (1950). The Neural Crest. Its Properties and Derivatives in the Light of Experimental Research. Oxford University Press, London.Google Scholar
  25. Huang, G.Y., Cooper, E.S., Waldo, K., Kirby, M.L., Gilula, N.B., and Lo, C.W. (1998). Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol 143:1725–1734.PubMedCrossRefGoogle Scholar
  26. Huang, G.-Y., and Lo, C.W. (1998). Modulation of neural crest migration by Cx43 mediated gap junctional communication.Google Scholar
  27. Jacobson, A.G., and Duncan, J.T. (1968). Heart induction in salamanders. Exp Zool 167: 79–103.CrossRefGoogle Scholar
  28. Kamino, K., Hirota, A., and Fujii, S. (1981). Localization of pacemaking activity in early embryonic heart monitored using voltage-sensitive dye. Nature 290:595–597.PubMedCrossRefGoogle Scholar
  29. Jiang, R.L., Lan, Y., Norton, C.R., Sundberg, J.P., and Gridley, T. (1998). The slug gene is not essential for mesoderm or neural crest development in mice. Dev Biol 198:277–285.PubMedGoogle Scholar
  30. Kirby, M.L. (1988a). Nodose placode contributes autonomic neurons to the heart in the absence of cardiac neural crest. J Neurosci 8:1089–1095.Google Scholar
  31. Kirby, M.L. (1988b). Nodose placode provides ectomesenchyme to the developing heart in the absence of cardiac neural crest. Cell Tissue Res 252:17–22.CrossRefGoogle Scholar
  32. Kirby, M.L. (1993). Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends Cardiovasc Med 3:18–23.PubMedCrossRefGoogle Scholar
  33. Kirby, M.L., Hunt, P., Wallis, K.T., and Thorogood, P. (1997). Normal development of the cardiac outflow tract is not dependent on normal patterning of the aortic arch arteries. Dev Dyn 208:34–47.PubMedCrossRefGoogle Scholar
  34. Kirby, M.L., Turnage, K.L., and Hays, B.M. (1985). Characterization of conotruncal malformations following ablation of “cardiac” neural crest. Anat Rec 213:87–93.PubMedCrossRefGoogle Scholar
  35. Kuratani, S.C., and Kirby, M.L. (1991). Initial migration and distribution of the cardiac neural crest in the avian embryo: an introduction to the concept of the circumpharyngeal crest. Am J Anat 191:215–227.PubMedCrossRefGoogle Scholar
  36. LaBonne, C., and Bronner-Fraser, M. (1998). Neural crest induction in Xenopus: evidence for a two-signal model. Development 125:2403–2414.PubMedGoogle Scholar
  37. Labosky, P.A., and Kaestner, K.H. (1998). The winged helix transcription factor Hfh2 is expressed in neural crest and spinal cord during mouse development. Mech Dev 76:185–190.PubMedCrossRefGoogle Scholar
  38. Leatherbury, L., Yun, J.S., and Wolfe, R. (1996). Association of abnormal configuration of the heart tube with depressed contractility after cardiac neural crest ablation. Ped Res 39:62A. Le Douarin, N. (1982). The Neural Crest. Cambridge University Press, Cambridge.Google Scholar
  39. Le Lièvre, C.S., and Le Douarin, N.M. (1975). Mesenchymal derivatives of the neuralcrest. Analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 34:125–154.PubMedGoogle Scholar
  40. Lev, M., Bharati, S., Meng, L., Liberthson, R.R., Paul, M.H., and Idriss, F.A. (1972). Aconcept of double-outlet right ventricle. J Thorac Cardiovasc Surg 64:271.PubMedGoogle Scholar
  41. Little, T.L., Beyer, E.C., and Duling, B.R. (1995). Connexin 43 and connexin 40 gapjunctional proteins are present in arteriolar smooth muscle and endothelium in vivo.Am J Physiol 268:H729–H739.PubMedGoogle Scholar
  42. Liu, J.P., and Jessell, T.M. (1998). A role for rhoB in the delamination of neural crest cells from the dorsal neural tube. Development 125:5055–5067.PubMedGoogle Scholar
  43. Lo, C.W., Cohen, M.F., Huang, G.Y., et al. (1997). Cx43 gap junction gene expression andgap junctional communication in mouse neural crest cells. Dev Genet 20:119–132.CrossRefGoogle Scholar
  44. Lo, C.W., Waldo, K.L., and Kirby, M.L. (1999). Gap junction communication and themodulation of cardiac neural crest cells. Trends Cardiovasc Med 9 (3–4):63–69.Google Scholar
  45. Lyons, G.E. (1994). In situ analysis of the cardiac muscle gene program during embryoge-nesis.Trends Cardiovasc Med 4:70–77.PubMedCrossRefGoogle Scholar
  46. Manasek, F.J. (1970). Histogenesis of the embryonic myocardium. AmJ Cardiol25:149–168. Mancilla, A., and Mayor, R. (1996). Neural crest formation in Xenopus laevis: mechanisms of Xslug induction. Dev Biol 177:580–590.Google Scholar
  47. Mangiacapra, F.J., Fransen, M.E., and Lemanski, L.F. (1995). Activin A and transforming growth factor-I3 stimulate heart formation in axolotls but do not rescue cardiac lethal mutants. Cell Tissue Res 282:227–236.PubMedCrossRefGoogle Scholar
  48. Marchant, L., Linker, C., Ruiz, P., Guerrero, N., and Mayor, R. (1998). The inductive properties of mesoderm suggest that the neural crest cells are specified by a BMP gradient. Dey Biol 198:319–329.Google Scholar
  49. Martinsen, B.J., and Bronner-Fraser, M. (1998). Neural crest specification regulated by the helix-loop-helix repressor Id2. Science 281:988–991.PubMedCrossRefGoogle Scholar
  50. Mayor, R., Guerrero, N., and Martínez, C. (1997). Role of FGF and noggin in neural crest induction. Dev Biol 189:1–12.PubMedCrossRefGoogle Scholar
  51. Mayor, R., Morgan, R., and Sargent, M.G. (1995). Induction of the prospective neural crest of Xenopus. Development 121:767–777.Google Scholar
  52. Meyer, D., and Birchmeier, C. (1995). Multiple essential functions of neuregulin in development. Nature 378:386–390.PubMedCrossRefGoogle Scholar
  53. Murphy, M., Reid, K., Furness, J.B., and Bartlett, P.F. (1994). FGF2 regulates proliferation of neural crest cells, with subsequent neuronal differentiation regulated by LIF or related factors. Development 120:3519–3528.PubMedGoogle Scholar
  54. Muslin, A.J., and Williams, L.T. (1991). Well-defined growth factors promote cardiac development in axolotl mesodermal explants. Development 112:1095–1101.PubMedGoogle Scholar
  55. Poelmann, R.E., Mikawa, T., and Gittenberger-de Groot, A.C. (1998). Neural crest cells in outflow tract septation of the embryonic chicken heart: differentiation and apoptosis. Dev Dyn 212:373–384.PubMedCrossRefGoogle Scholar
  56. Robertson, K., and Mason, I. (1995). Expression of ret in the chicken embryo suggests roles in regionalisation of the vagal neural tube and somites and in development of multiple neural crest and placodal lineages. Mech Dev 53:329–344.PubMedCrossRefGoogle Scholar
  57. Romanoff, A.L. (1960). The Avian Embryo: Structural and Functional Development. New York: The Macmillan Company.Google Scholar
  58. Sater, A.K., and Jacobson, A.G. (1990). The restriction of the heart morphogenetic field in Xenopus laevis. Dev Biol 140:328–336.CrossRefGoogle Scholar
  59. Scherson, T., Serbedzija, G., Fraser, S., and Bronner-Fraser, M. (1993). Regulative capacity of the cranial neural tube to form neural crest. Development 118:1049–1062. Schultheiss, T.M., Burch, J.B.E., and Lassar, A.B. (1997). A role for bone morphogeneticproteins in the induction of cardiac myogenesis.Genes Dev 11:451–462.Google Scholar
  60. Sieber-Blum, M., and Zhang, J.M. (1997). Growth factor action in neural crest cell diversification. J Anat 191:493–499.PubMedCrossRefGoogle Scholar
  61. Stocker, K.M., Sherman, L., Rees, S., and Ciment, G. (1991). Basic FGF and TGF-(31 influence commitment to melanogenesis in neural crest-derived cells of avian embryos. Development 111:635–645.PubMedGoogle Scholar
  62. Sugi, Y., Sasse, J., Barron, M., and Lough, J. (1995). Developmental expression of fibroblast growth factor receptor-1 (cek-1;flg) during heart development. Dev Dyn 202:115–125. Suzuki, H.R., and Kirby, M.L. (1997). Absence of neural crest cell regeneration from the postotic neural tube. Dev Biol 184:222–233.Google Scholar
  63. Tokuyasu, T.K., and Maher, P.A. (1987). Immunocytochemical studies of cardiac myofibrillogenesis in early chick embryos. I. Presence of immunofluorescent titin spots in premyofibril stages. J Cell Biol 105:2781–2793.PubMedCrossRefGoogle Scholar
  64. Tomita, H., Connuck, D.M., Leatherbury, L., and Kirby, M.L. (1991). Relation of early hemodynamic changes to final cardiac phenotype and survival after neural crest ablation in chick embryos. Circulation 84:1289–1295.PubMedCrossRefGoogle Scholar
  65. Waldo, K.L., Kumiski, D., and Kirby, M.L. (1996). Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Dev Dyn 205:281–292.PubMedCrossRefGoogle Scholar
  66. Waldo, K.L., Lo, C.W., and Kirby, M.L. (1999a). Cx43 expression reflects neural crestpatterns during cardiovascular development. Dev Biol 208:307–323.PubMedCrossRefGoogle Scholar
  67. Waldo, K.L., Miyagawa-Tomita, S., Kumiski, D., and Kirby, M.L. (1998). Cardiac neural crest cells provide new insight into septation of the outflow tract: aortic sac to ventricular septal closure. Dev Biol 196:2129–2144.CrossRefGoogle Scholar
  68. Waldo, K.L., Zdanowicz, M., Burch, J., Kumiski, D.H., Godt, R.E., Creazzo, T.L., and Kirby, M.L. (1999b). A novel role for cardiac neural crest in heart development. J Clin Invest 103:1499–1507.CrossRefGoogle Scholar
  69. Wrenn, R.W., Raeuber, C.L., Herman, I.E., Walton, W.J., and Rosenquist, T.H. (1993). Transforming growth factor-beta: Signal transduction via protein kinase C in cultured embryonic vascular smooth muscle cells. In Vitro Cell Dev Biol 29A:73–78.PubMedCrossRefGoogle Scholar
  70. Zhu, X., Sasse, J., McAllister, D., and Lough, J. (1996). Evidence that fibroblast growth factors 1 and 4 participate in regulation of cardiogenesis. Dev Dyn 207:429–438.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Margaret L. Kirby

There are no affiliations available

Personalised recommendations