Skip to main content

Advertisement

SpringerLink
Log in

Notch Signaling in Cardiac Development and Disease

  • Riley Symposium
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

The Notch pathway is an ancient, highly conserved signaling mechanism that participates in essential cell–cell communication events between adjacent cells. Mutations in Notch-signaling elements cause cardiac abnormalities in mice and humans, demonstrating an essential role for Notch in heart development. Studies with targeted mutant mice indicate that Notch signaling promotes the epithelial-to-mesenchyme transition that gives rise to the cardiac valve primordium, which later is sculpted into mature valves. During ventricular chamber development, the myocardium differentiates into two layers: an outer compact zone and an inner trabecular zone. Trabeculae provide a pumping function during early phases of ventricular development and contribute to the cardiac conduction system in the mature heart. Notch regulates the endocardium-to-myocardium signals that balance proliferation and differentiation of trabecular myocytes. Recent evidence demonstrates that defective NOTCH signaling leads to aortic valve degeneration in humans. Future research will be informative about the involvement of altered NOTCH signaling in chamber abnormalities and other cardiac disorders.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    Article  PubMed  CAS  Google Scholar 

  2. Beis D, Bartman T, Jin SW et al (2005) Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development. Development 132:4193–4204

    Article  PubMed  CAS  Google Scholar 

  3. Ben-Shachar G, Arcilla RA, Lucas RV et al (1985) Ventricular trabeculations in the chick embryo heart and their contribution to ventricular and muscular septal development. Circ Res 57:759–766

    PubMed  CAS  Google Scholar 

  4. Bettenhausen B, Hrabe de Angelis M, Simon D et al (1995) Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila delta. Development 121:2407–2418

    PubMed  CAS  Google Scholar 

  5. Blank V, Kourilsky P, Israel A (1992) NF-kappa B and related proteins: Rel/dorsal homologies meet ankyrin-like repeats. Trends Biochem Sci 17:135–140

    Article  PubMed  CAS  Google Scholar 

  6. Bolos V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363

    Article  PubMed  CAS  Google Scholar 

  7. Bruckner K, Perez L, Clausen H et al (2000) Glycosyltransferase activity of Fringe modulates Notch–Delta interactions. Nature 406:411–415

    Article  PubMed  CAS  Google Scholar 

  8. Chen F, Kook H, Milewski R et al (2002) Hop is an unusual homeobox gene that modulates cardiac development. Cell 110:713–723

    Article  PubMed  CAS  Google Scholar 

  9. Chen H, Shi S, Acosta L et al (2004) BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131:2219–2231

    Article  PubMed  CAS  Google Scholar 

  10. De Strooper B, Annaert W, Cupers P et al (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–522

    Article  PubMed  CAS  Google Scholar 

  11. Del Amo FF, Smith DE, Swiatek PJ et al (1992) Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development. Development 115:737–744

    PubMed  CAS  Google Scholar 

  12. Del Monte G, Grego-Bessa J, Gonzalez-Rajal A et al (2007) Monitoring Notch1 activity in development: evidence for a feedback regulatory loop. Dev Dyn 236:2594–2614

    Article  PubMed  CAS  Google Scholar 

  13. Dunwoodie SL, Henrique D, Harrison SM et al (1997) Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124:3065–3076

    PubMed  CAS  Google Scholar 

  14. Eldadah ZA, Hamosh A, Biery NJ et al (2001) Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet 10:163–169

    Article  PubMed  CAS  Google Scholar 

  15. Fehon RG, Kooh PJ, Rebay I et al (1990) Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61:523–534

    Article  PubMed  CAS  Google Scholar 

  16. Fischer A, Schumacher N, Maier M et al (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18:901–911

    Article  PubMed  CAS  Google Scholar 

  17. Fischer A, Steidl C, Wagner TU et al (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 100:856–863

    Article  PubMed  CAS  Google Scholar 

  18. Garg V, Muth AN, Ransom JF et al (2005) Mutations in Notch1 cause aortic valve disease. Nature 437:270–274

    Article  PubMed  CAS  Google Scholar 

  19. Grego-Bessa J, Luna-Zurita L, del Monte G et al (2007) Notch signaling is essential for ventricular chamber development. Dev Cell 12:415–429

    Article  PubMed  CAS  Google Scholar 

  20. Hertig CM, Kubalak SW, Wang Y et al (1999) Synergistic roles of neuregulin-1 and insulin-like growth factor-1 in activation of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis. J Biol Chem 274:37362–37369

    Article  PubMed  CAS  Google Scholar 

  21. Jenni R, Oechslin E, Schneider J et al (2001) Echocardiographic and pathoanatomical characteristics of isolated left ventricular noncompaction: a step towards classification as a distinct cardiomyopathy. Heart 86:666–671

    Article  PubMed  CAS  Google Scholar 

  22. Kokubo H, Miyagawa-Tomita S, Johnson RL (2005) Hesr, a mediator of the notch signaling functions in heart and vessel development. Trends Cardiovasc Med 15:190–194

    Article  PubMed  CAS  Google Scholar 

  23. Kokubo H, Miyagawa-Tomita S, Nakazawa M et al (2005) Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev Biol 278:301–309

    Article  PubMed  CAS  Google Scholar 

  24. Kokubo H, Miyagawa-Tomita S, Tomimatsu H et al (2004) Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Circ Res 95:540–547

    Article  PubMed  CAS  Google Scholar 

  25. Kokubo H, Tomita-Miyagawa S, Hamada Y et al (2007) Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development 134:747–755

    Article  PubMed  CAS  Google Scholar 

  26. Krebs LT, Xue Y, Norton CR et al (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343–1352

    PubMed  CAS  Google Scholar 

  27. Kurooka H, Honjo T (2000) Functional interaction between the mouse Notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem 275:17211–17220

    Article  PubMed  CAS  Google Scholar 

  28. Lardelli M, Dahlstrand J, Lendahl U (1994) The novel Notch homologue mouse Notch3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev 46:123–136

    Article  PubMed  CAS  Google Scholar 

  29. Lewis J (1998) Notch signaling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 9:583–589

    Article  PubMed  CAS  Google Scholar 

  30. Lindsell CE, Shawber CJ, Boulter J et al (1995) Jagged: a mammalian ligand that activates Notch1. Cell 80:909–917

    Article  PubMed  CAS  Google Scholar 

  31. Logeat F, Bessia C, Brou C et al (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 95:8108–8112

    Article  PubMed  CAS  Google Scholar 

  32. Loomes KM, Underkoffler LA, Morabito J et al (1999) The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. Hum Mol Genet 8:2443–2449

    Article  PubMed  CAS  Google Scholar 

  33. McCright B, Gao X, Shen L et al (2001) Defects in development of the kidney, heart, and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128:491–502

    PubMed  CAS  Google Scholar 

  34. McCright B, Lozier J, Gridley T (2002) A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129:1075–1082

    PubMed  CAS  Google Scholar 

  35. McDaniell R, Warthen DM, Sanchez-Lara PA et al (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79:169–173

    Article  PubMed  CAS  Google Scholar 

  36. McLaughlin KA, Rones MS, Mercola M (2000) Notch regulates cell fate in the developing pronephros. Dev Biol 227:567–580

    Article  PubMed  CAS  Google Scholar 

  37. Milan DJ, Giokas AC, Serluca FC et al (2006) Notch1b and neuregulin are required for specification of central cardiac conduction tissue. Development 133:1125–1132

    Article  PubMed  CAS  Google Scholar 

  38. Moloney DJ, Panin VM, Johnston SH et al (2000) Fringe is a glycosyltransferase that modifies Notch. Nature 406:369–375

    Article  PubMed  CAS  Google Scholar 

  39. Morel V, Lecourtois M, Massiani O et al (2001) Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Curr Biol 11:789–792

    Article  PubMed  CAS  Google Scholar 

  40. Mumm JS, Schroeter EH, Saxena MT et al (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5:197–206

    Article  PubMed  CAS  Google Scholar 

  41. Nakagawa O, Nakagawa M, Richardson JA et al (1999) HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev Biol 216:72–84

    Article  PubMed  CAS  Google Scholar 

  42. Nemir M, Croquelois A, Pedrazzini T et al (2006) Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling. Circ Res 98:1471–1478

    Article  PubMed  CAS  Google Scholar 

  43. Oka C, Nakano T, Wakeham A et al (1995) Disruption of the mouse RBP-J kappa gene results in early embryonic death. Development 121:3291–3301

    PubMed  CAS  Google Scholar 

  44. Panin VM, Papayannopoulos V, Wilson R et al (1997) Fringe modulates Notch–ligand interactions. Nature 387:908–912

    Article  PubMed  CAS  Google Scholar 

  45. Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767

    Article  PubMed  CAS  Google Scholar 

  46. Rechsteiner M (1988) Regulation of enzyme levels by proteolysis: the role of pest regions. Adv Enzyme Regul 27:135–151

    Article  PubMed  CAS  Google Scholar 

  47. Rentschler S, Zander J, Meyers K et al (2002) Neuregulin-1 promotes formation of the murine cardiac conduction system. Proc Natl Acad Sci U S A 99:10464–10469

    Article  PubMed  CAS  Google Scholar 

  48. Runyan RB, Markwald RR (1983) Invasion of mesenchyme into three-dimensional collagen gels: a regional and temporal analysis of interaction in embryonic heart tissue. Dev Biol 95:108–114

    Article  PubMed  CAS  Google Scholar 

  49. Rutenberg JB, Fischer A, Jia H et al (2006) Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133:4381–4390

    Article  PubMed  CAS  Google Scholar 

  50. Sakata Y, Kamei CN, Nakagami H et al (2002) Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc Natl Acad Sci U S A 99:16197–16202

    Article  PubMed  CAS  Google Scholar 

  51. Shawber C, Boulter J, Lindsell CE et al (1996) Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol 180:370–376

    Article  PubMed  CAS  Google Scholar 

  52. Shin CH, Liu ZP, Passier R et al (2002) Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110:725–735

    Article  PubMed  CAS  Google Scholar 

  53. Stollberger C, Finsterer J, Blazek G (2002) Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 90:899–902

    Article  PubMed  Google Scholar 

  54. Swiatek PJ, Lindsell CE, del Amo FF et al (1994) Notch1 is essential for postimplantation development in mice. Genes Dev 8:707–719

    Article  PubMed  CAS  Google Scholar 

  55. Tamura K, Taniguchi Y, Minoguchi S et al (1995) Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol 5:1416–1423

    Article  PubMed  CAS  Google Scholar 

  56. Timmerman LA, Grego-Bessa J, Raya A et al (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18:99–115

    Article  PubMed  CAS  Google Scholar 

  57. Uyttendaele H, Marazzi G, Wu G et al (1996) Notch4/int-3, a mammary protooncogene, is an endothelial cell-specific mammalian Notch gene. Development 122:2251–2259

    PubMed  CAS  Google Scholar 

  58. Venkatesh DA, Park KS, Harrington A et al (2008) Cardiovascular and hematopoietic defects associated with Notch1 activation in embryonic Tie2-expressing populations. Circ Res 103:423–431

    Article  PubMed  CAS  Google Scholar 

  59. Vuillemin M, Pexieder T (1989) Normal stages of cardiac organogenesis in the mouse: II. Development of the internal relief of the heart. Am J Anat 184:114–128

    CAS  Google Scholar 

  60. Watanabe Y, Kokubo H, Miyagawa-Tomita S et al (2006) Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse. Development 133:1625–1634

    Article  PubMed  CAS  Google Scholar 

  61. Weinmaster G, Roberts VJ, Lemke G (1992) Notch2: a second mammalian Notch gene. Development 116:931–941

    PubMed  CAS  Google Scholar 

  62. Wilson A, Radtke F (2006) Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett 580:2860–2868

    Article  PubMed  CAS  Google Scholar 

  63. Wu L, Aster JC, Blacklow SC et al (2000) MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 26:484–489

    Article  PubMed  CAS  Google Scholar 

  64. Zhao YY, Sawyer DR, Baliga RR et al (1998) Neuregulins promote survival and growth of cardiac myocytes: persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 273:10261–10269

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The study was supported by grants SAF2007-62445 from the Spanish Ministry of Science and Innovation, S-BIO-0194/06 from the Regional Government of Madrid, RETICS 06/0014/0038 from the Spanish Ministry of Science and Innovation, and LSHM-CT-2005-018630 from the European Union 6th FP and the Fundación Rodríguez Pascual.

Author information

Authors and Affiliations

  1. Laboratorio de Biología Celular y del Desarrollo, Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Darwin 3, Campus de Cantoblanco, 28049, Madrid, Spain

    José Luis de la Pompa

Authors
  1. José Luis de la Pompa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Luis de la Pompa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de la Pompa, J.L. Notch Signaling in Cardiac Development and Disease. Pediatr Cardiol 30, 643–650 (2009). https://doi.org/10.1007/s00246-008-9368-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-008-9368-z

Keywords

Search

Navigation