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:

The multifaceted role of Notch in cardiac development and disease

Key Points

  • Human mutations in Notch signalling components have been implicated in several forms of congenital cardiovascular disease, including cardiac outflow tract defects (jagged 1, notch 2), aortic valve disease (notch 1), cardiomyopathy (presenilin 1 and 2), and cerebral arteriopathy (notch 3).

  • Emerging evidence shows that Notch has many distinct roles during cardiac development. The outcome of Notch signalling varies according to cell type and stage of development. Notch inhibits the differentiation of cardiomyocytes from mesoderm in embryos and embryonic stem cells.

  • Notch and/or its target genes of the Hes-related transcription factor (Hrt) family are necessary for boundary formation in the developing atrioventricular canal.

  • Notch promotes epithelial-to-mesenchymal transition in the developing heart valves by upregulating Snail and Slug expression, promoting the loss of adhesion proteins, and inducing the expression of mesenchymal markers.

  • Notch activity in the endocardium promotes ventricular trabeculation by inducing the expression of ephrin B2 and bone morphogenetic protein 10 (BMP10), which promote the proliferation and differentiation of adjacent myocardial cells.

  • Notch is required in cardiac neural crest cells for the specification of smooth muscle cell fate and for the proper morphogenesis of the cardiac outflow tract.

  • Hrt genes are the best studied Notch targets in the heart; here they have crucial functions in cardiac morphogenesis by regulating chamber-specific gene expression, atrioventricular canal development and valve formation. However, some Hrt genes might be regulated in a Notch-independent manner.

  • Not all Notch-related phenotypes can be explained by Hrt gene activity, indicating that additional unidentified Notch target genes might be essential for cardiac development.

  • Understanding the functions of Notch in cardiac development has implications for understanding congenital and adult heart disease, and shows potential for developing new therapeutic strategies for heart failure and cardiac repair.

Abstract

Notch receptors and their cognate ligands transduce crucial signals between cells in various tissues, and have been conserved across millions of years of evolution. Mutations in Notch signalling components result in congenital heart defects in humans and mice, demonstrating an essential role for Notch in cardiovascular development. The results of recent experiments implicate this signalling pathway in many stages of heart development, and provide mechanistic insight into the vital functions of Notch in the aetiology of several common forms of paediatric and adult cardiac disease.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Notch in development of the atrioventricular canal and endocardial cushions.
Figure 2: Notch and ventricular trabeculation.
Figure 3: Notch and cardiac outflow tract development.

Similar content being viewed by others

References

  1. Bray, S. J. Notch signalling: a simple pathway becomes complex. Nature Rev. Mol. Cell Biol. 7, 678–689 (2006).

    Article  CAS  Google Scholar 

  2. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for NOTCH1. Nature Genet. 16, 243–251 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet. 16, 235–242 (1997). References 2 and 3 demonstrate that Alagille syndrome is caused by mutations in the human JAG1 gene, providing evidence that mutations in a Notch signalling component could be linked to congenital heart defects.

    Article  CAS  PubMed  Google Scholar 

  4. Garg, V. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 437, 270–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Joutel, A. et al. NOTCH3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707–710 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Krantz, I. D. et al. JAGGED1 mutations in patients ascertained with isolated congenital heart defects. Am. J. Med. Genet. 84, 56–60 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, D. et al. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am. J. Med. Genet. 79, 1030–1039 (2006).

    CAS  Google Scholar 

  10. Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Duarte, A. et al. Dosage-sensitive requirement for mouse DLL4 in artery development. Genes Dev. 18, 2474–2478 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gale, N. W. et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl Acad. Sci. USA 101, 15949–15954 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krebs, L. T. et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 18, 2469–2473 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand JAGGED1. Hum. Mol. Genet. 8, 723–730 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Gridley, T. Notch signaling in vascular development and physiology. Development 134, 2709–2718 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Hofmann, J. J. & Iruela-Arispe, M. L. Notch signaling in blood vessels: who is talking to whom about what? Circ. Res. 100, 1556–1568 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Nemir, M., Croquelois, A., Pedrazzini, T. & Radtke, F. Induction of cardiogenesis in embryonic stem cells via downregulation of NOTCH1 signaling. Circ. Res. 98, 1471–1478 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Schroeder, T. et al. Activated NOTCH1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development. Mech. Dev. 123, 570–579 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Schroeder, T. et al. Recombination signal sequence-binding protein jκ alters mesodermal cell fate decisions by suppressing cardiomyogenesis. Proc. Natl Acad. Sci. USA 100, 4018–4023 (2003). This work shows that manipulation of the Notch signalling pathway can be used as a tool to influence cardiac cell-fate specification in cultured ES cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Park, M., Yaich, L. E. & Bodmer, R. Mesodermal cell fate decisions in Drosophila are under the control of the lineage genes numb, Notch, and sanpodo. Mech. Dev. 75, 117–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. 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). This study, using X. laevis embryos, was the first to show that Notch inhibits cardiogenesis in a vertebrate model.

    CAS  PubMed  Google Scholar 

  23. Han, Z. & Bodmer, R. Myogenic cell fates are antagonized by Notch only in asymmetric lineages of the Drosophila heart, with or without cell division. Development 130, 3039–3051 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Chau, M. D. L., Tuft, R., Fogarty, K. & Bao, Z.-Z. Notch signaling plays a key role in cardiac cell differentiation. Mech. Dev. 123, 626–640 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watanabe, Y. et al. Activation of NOTCH1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse. Development 133, 1625–1634 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Black, B. L. & Olson, E. N. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell Dev. Biol. 14, 167–196 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Wilson-Rawls, J., Molkentin, J. D., Black, B. L. & Olson, E. N. Activated Notch inhibits myogenic activity of the MADS-box transcription factor myocyte enhancer factor 2C. Mol. Cell. Biol. 19, 2853–2862 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shen, H. et al. The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. Genes Dev. 675–688 (2006).

    Article  CAS  Google Scholar 

  29. 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 

  30. Harrelson, Z. et al. TBX2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131, 5041–5052 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Yamada, M., Revelli, J.-P., Eichele, G., Barron, M. & Schwartz, R. J. Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx-2. Dev. Biol. 228, 95–105 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Rutenberg, J. B. et al. Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133, 4381–4390 (2006). References 32 and 33 propose a mechanism by which HRT1 and HRT2 create boundaries in the developing AV canal.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Nieto, M. A. The Snail superfamily of zinc-finger transcription factors. Nature Rev. Mol. Cell Biol. 3, 155–166 (2002).

    Article  CAS  Google Scholar 

  36. Timmerman, L. A. et al. Notch promotes epithelial–mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004). Describes the role of Notch in EMT during heart valve development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Noseda, M. et al. Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation. Circ. Res. 94, 910–917 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Mohamed, S. A. et al. Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem. Biophys. Res. Commun. 345, 1460–1465 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Rajamannan, N. M., Gersh, B. & Bonow, R. O. Calcific aortic stenosis: from bench to the bedside — emerging clinical and cellular concepts. Heart 89, 801–805 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wang, H. U., Chen, Z.-F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. 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 

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

    Article  CAS  PubMed  Google Scholar 

  43. Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ERBB4 neuregulin receptor. Nature 378, 390–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, H. et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131, 2219–2231 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Grego-Bessa, J. et al. Notch signaling is essential for ventricular chamber development. Dev. Cell 12, 415–429 (2007). This paper outlines a genetic pathway by which Notch signalling in the endocardium promotes the differentiation and proliferation of adjacent cardiomyocytes during ventricular chamber development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McElhinney, D. B. et al. Analysis of cardiovascular phenotype and genotype–phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation 106, 2567–2574 (2002).

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Nakajima, M., Moriizumi, E., Koseki, H. & Shirasawa, T. Presenilin 1 is essential for cardiac morphogenesis. Dev. Dyn. 230, 795–799 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Kopan, R. & Ilagan, M. X. G. γ-secretase: proteasome of the membrane? Nature Rev. Mol. Cell Biol. 5, 499–504 (2004).

    Article  CAS  Google Scholar 

  50. Stoller, J. Z. & Epstein, J. A. Cardiac neural crest. Semin. Cell Dev. Biol. 16, 704 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Buckingham, M. E., Meilhac, S. & Zaffran, S. Building the mammalian heart from two sources of myocardial cells. Nature Rev. Genet. 6, 826–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. High, F. A. et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J. Clin. Invest. 117, 353–363 (2007). This study demonstrates a requirement for Notch in cardiac neural crest cells during outflow tract development, and describes Notch's role in the differentiation of neural crest cells into vascular smooth muscle.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cornell, R. A. & Eisen, J. S. Notch in the pathway: the roles of Notch signaling in neural crest development. Semin. Cell Dev. Biol. 16, 663–672 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Kamath, B. M. et al. Vascular anomalies in Alagille Syndrome, a significant cause of morbidity and mortality. Circulation 109, 1354–1358 (2004).

    Article  PubMed  Google Scholar 

  55. Doi, H. et al. Jagged1-selective Notch signaling induces smooth muscle differentiation via a RBP-J.κ-dependent pathway. J. Biol. Chem. 281, 28555–28564 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Noseda, M. et al. Smooth muscle α-actin is a direct target of Notch/CSL. Circ. Res. 98, 1468–1470 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Domenga, V. et al. NOTCH3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730–2735 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Doi, H. et al. HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Arterioscler. Thromb. Vasc. Biol. 25, 2328–2334 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Proweller, A., Pear, W. S. & Parmacek, M. S. Notch signaling represses myocardin-induced smooth muscle cell differentiation. J. Biol. Chem. 280, 8994–9004 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Iso, T., Kedes, L. & Hamamori, Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J. Cell. Physiol. 194, 237–255 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Iso, T., Chung, G., Hamamori, Y. & Kedes, L. HERP1 is a cell type-specific primary target of Notch. J. Biol. Chem. 277, 6598–6607 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Iso, T. et al. HERP, a new primary target of Notch regulated by ligand binding. Mol. Cell. Biol. 21, 6071–6079 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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 

  65. 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 

  66. Kokubo, 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  CAS  PubMed  Google Scholar 

  67. Leimeister, C., Schumacher, N., Steidl, C. & Gessler, M. Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos. Mech. Dev. 98, 175–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Sakata, Y. et al. Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc. Natl Acad. Sci. USA 99, 16197–16202 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kokubo, H. et al. Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Circ. Res. 95, 540–547 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Gessler, M. et al. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2−/− mice. Curr. Biol. 12, 1601–1604 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Donovan, J., Kordylewska, A., Jan, Y. N. & Utset, M. F. Tetralogy of Fallot and other congenital heart defects in Hey2 mutant mice. Curr. Biol. 12, 1605–1610 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Fischer, A. et al. Phenotypic variability in Hey2−/− mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mamm. Genome 15, 711–716 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Sakata, Y. et al. The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation. J. Mol. Cell. Cardiol. 40, 267–273 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Xin, M. et al. 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 104, 7975–7980 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Koibuchi, N. & Chin, M. T. CHF1/HEY2 plays a pivotal role in left ventricular maturation through suppression of ectopic atrial gene expression. Circ. Res. 100, 850–855 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 18, 901–911 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kokubo, H., Miyagawa-Tomita, S., Nakazawa, M., Saga, Y. & Johnson, R. L. Mouse Hesr1 and Hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev. Biol. 278, 301–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Fischer, A. et al. Combined loss of Hey1 and HeyL Causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ. Res. 100, 856–863 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Fischer, A. et al. Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Mol. Cell. Biol. 25, 8960–8970 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kathiriya, I. S. et al. Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism. J. Biol. Chem. 279, 54937–54943 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Xiang, F. et al. Transcription factor CHF1/HEY2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4. Am. J. Physiol. Heart Circ. Physiol. 290, H1997–H2006 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Itoh, F. et al. Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. EMBO J. 23, 541–551 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dahlqvist, C. et al. Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation. Development 130, 6089–6099 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Hurlbut, G. D., Kankel, M. W., Lake, R. J. & Artavanis-Tsakonas, S. Crossing paths with Notch in the hyper-network. Curr. Opin. Cell Biol. 19, 166–175 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Parmacek, M. S. & Epstein, J. A. Pursuing cardiac progenitors: regeneration redux. Cell 120, 295–298 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Chiba, S. Notch signaling in stem cell systems. Stem Cells 24, 2437–2447 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Vasyutina, E. et al. RBP-J. (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells. Proc. Natl Acad. Sci. USA 104, 4443–4448 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schuster-Gossler, K., Cordes, R. & Gossler, A. Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants. Proc. Natl Acad. Sci. USA 104, 537–542 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Luo, D., Renault, V. M. & Rando, T. A. The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. Semin. Cell Dev. Biol. 16, 612–622 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Urbanek, K. et al. Stem cell niches in the adult mouse heart. Proc. Natl Acad. Sci. USA 103, 9226–9231 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Raya, A. et al. Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proc. Natl Acad. Sci. USA 100, 11889–11895 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lien, C.-L., Schebesta, M., Makino, S., Weber, G. J. & Keating, M. T. Gene expression analysis of zebrafish heart regeneration. PLoS Biol. 4, e260 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fischer, A. & Gessler, M. Delta–Notch — and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucl. Acids Res. 35, 4583–4596 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kadesch, T. Notch signaling: the demise of elegant simplicity. Curr. Opin. Genet. Dev. 14, 506–512 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Conlon, R. A., Reaume, A. G. & Rossant, J. NOTCH1 is required for the coordinate segmentation of somites. Development 121, 1533–1545 (1995).

    CAS  PubMed  Google Scholar 

  99. Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G. & Gridley, T. Notch1 is essential for postimplantation development in mice. Genes Dev. 8, 707–719 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Hamada, Y. et al. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 126, 3415–3424 (1999).

    CAS  PubMed  Google Scholar 

  101. Hrabe de Angelis, M., McIntyre, J. & Gossler, A. Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386, 717–721 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Dunwoodie, S. L. et al. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 129, 1795–1806 (2002).

    CAS  PubMed  Google Scholar 

  103. Kusumi, K. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genet. 19, 274–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Jiang, R. et al. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev. 12, 1046–1057 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Oka, C. et al. Disruption of the mouse RBP-J.κ gene results in early embryonic death. Development 121, 3291–3301 (1995).

    CAS  PubMed  Google Scholar 

  106. Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Donoviel, D. B. et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801–2810 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Herreman, A. et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc. Natl Acad. Sci. USA 96, 11872–11877 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jonathan A. Epstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alagille syndrome

FURTHER INFORMATION

Jonathan A. Epstein's homepage

Glossary

Trabeculae

Specialized sheets of myocardium forming protrusions that line the inside of the ventricles.

Sarcomeric

Pertaining to the sarcomere, the contractile unit composed of actin and myosin fibres within muscle cells.

Hypocellular

Having fewer cells than is seen in normal structures.

Haploinsufficiency

When loss of function of one gene copy leads to an abnormal phenotype.

Bicuspid aortic valve

An aortic valve that has only two leaflets instead of three. This congenital disorder often leads to valve calcification or degeneration with ageing.

Aortic valve calcification

Hardening of the aortic valve leaflets due to deposition of calcium-containing substances, which can result in a narrowing of the valve orifice or compromised valve function.

Tetralogy of Fallot

A congenital heart disorder characterized by a hole in the septum that normally separates the left and right ventricles, an abnormally located connection between the left ventricle and the aorta, a narrowed connection between the right ventricle and the pulmonary artery, and an enlarged right ventricle.

Cell-autonomous

Describes a genetic trait in which only genotypically mutant cells show the mutant phenotype.

Atresia

Failure to form a structure during development.

Congestive heart failure

The inability of the heart to pump enough blood to meet the demands of the body, resulting in elevated venous pressures and congestion of blood in the liver.

Rights and permissions

Reprints and permissions

About this article

Cite this article

High, F., Epstein, J. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet 9, 49–61 (2008). https://doi.org/10.1038/nrg2279

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2279

This article is cited by

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