International Journal of Hematology

, Volume 82, Issue 4, pp 277–284 | Cite as

Paradigms of Notch Signaling in Mammals

  • Alexis Dumortier
  • Anne Wilson
  • H. Robson MacDonald
  • Freddy Radtke


Notch proteins regulate a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. These proteins are involved in organogenesis during embryonic development as well as in the maintenance of homeostasis of self-renewing systems. The paradigms of Notch function, such as stem and progenitor cell maintenance, lineage specification mediated by binary cell fate decisions, and induction of terminal differentiation, were initially established in invertebrates and subsequently confirmed in mammals. Moreover, aberrant Notch signaling is linked to tumorigenesis. In this review, we discuss the origin of postulated Notch functions, give examples from different mammalian organ systems, and try to relate them to the hematopoietic system.

Key words

Notch Hematopoiesis Stem cell Binary cell fate specification Differentiation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Morgan TH. The theory of the gene.Am Nat. 1917;51:513–544.CrossRefGoogle Scholar
  2. 2.
    Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats.Cell. 1985;43:567–581.CrossRefPubMedGoogle Scholar
  3. 3.
    Kidd S, Kelley MR, Young MW. Sequence of the Notch locus ofDrosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors.Mol Cell Biol. 1986;6:3094–3108.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Greenwald I. LIN-12/Notch signaling: lessons from worms and flies.Genes Dev. 1998;12:1751–1762.CrossRefPubMedGoogle Scholar
  5. 5.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development.Science. 1999;284:770–776.CrossRefPubMedGoogle Scholar
  6. 6.
    Parks AL, Klueg KM, Stout JR, Muskavitch MA. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway.Development. 2000;127:1373–1385.PubMedGoogle Scholar
  7. 7.
    Fortini ME. γ-Secretase-mediated proteolysis in cell-surface-receptor signalling.Nat Rev Mol Cell Biol. 2002;3:673–684.CrossRefPubMedGoogle Scholar
  8. 8.
    Selkoe D, Kopan R. Notch and Presenilin: regulated intramem-brane proteolysis links development and degeneration.Annu Rev Neurosci. 2003;26:565–597.CrossRefPubMedGoogle Scholar
  9. 9.
    Periz G, Fortini ME. Functional reconstitution of γ-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2.J Neurosci Res. 2004;77:309–322.CrossRefPubMedGoogle Scholar
  10. 10.
    Jeffries S, Robbins DJ, Capobianco AJ. Characterization of a high-molecular-weight Notch complex in the nucleus.Mol Cell Biol. 2002;11:3927–3941.CrossRefGoogle Scholar
  11. 11.
    Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue ofDrosophila Mastermind, is a transcriptional co-activator for NOTCH receptors.Nat Genet. 2000;26:484–489.CrossRefPubMedGoogle Scholar
  12. 12.
    Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.Genes Dev. 2002;16:1397–1411.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Davis RL, Turner DL. Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning.Oncogene. 2001;20:8342–8357.CrossRefPubMedGoogle Scholar
  14. 14.
    Ishibashi M. Molecular mechanisms for morphogenesis of the central nervous system in mammals.Anat Sci Int. 2004;79:226–234.CrossRefPubMedGoogle Scholar
  15. 15.
    Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway.J Cell Physiol. 2003;194:237–255.CrossRefPubMedGoogle Scholar
  16. 16.
    Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.EMBO J. 2001;20:3427–3436.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Krebs LT, Deftos ML, Bevan MJ, Gridley T. TheNrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the Notch signaling pathway.Dev Biol. 2001;238:110–119.CrossRefPubMedGoogle Scholar
  18. 18.
    Deftos ML, Huang E, Ojala EW, Forbush KA, Bevan MJ. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymo-cytes.Immunity. 2000;13:73–84.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Reizis B, Leder P. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway.Genes Dev. 2002;16:295–300.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kraman M, McCright B. Functional conservation of Notch1 and Notch2 intracellular domains.FASEB J. 2005;19:1311–1313.CrossRefPubMedGoogle Scholar
  21. 21.
    Okajima T, Irvine KD. Regulation of Notch signaling byO-linked fucose.Cell. 2002;111:893–904.CrossRefPubMedGoogle Scholar
  22. 22.
    Okajima T, Xu A, Lei L, Irvine KD. Chaperone activity of proteinO-fucosyltransferase 1 promotes Notch receptor folding.Science. 2005;307:1599–1603.CrossRefPubMedGoogle Scholar
  23. 23.
    Haltiwanger RS, Stanley P. Modulation of receptor signaling by glycosylation: fringe is anO-fucose-β1,3-N-acetylglucosaminyl-transferase.Biochim Biophys Acta. 2002;1573:328–335.CrossRefPubMedGoogle Scholar
  24. 24.
    Haines N, Irvine K. Glycosylation regulates Notch signalling.Nat Rev Mol Cell Biol. 2003;4:786–797.CrossRefPubMedGoogle Scholar
  25. 25.
    Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S. Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats.Development. 1995;121:2633–2644.PubMedGoogle Scholar
  26. 26.
    Izon DJ, Aster JC, He Y, et al. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.Immunity. 2002;16:231–243.CrossRefPubMedGoogle Scholar
  27. 27.
    Frise E, Knoblich JA, Younger-Shepherd S, Jan LY, Jan YN. TheDrosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage.Proc Natl AcadSci USA. 1996;93:11925–11932.CrossRefGoogle Scholar
  28. 28.
    Yun TJ, Bevan MJ. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.J Immunol. 2003;170:5834–5841.CrossRefPubMedGoogle Scholar
  29. 29.
    Kuroda K, Han H, Tani S, et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway.Immunity. 2003;18:301–312.CrossRefPubMedGoogle Scholar
  30. 30.
    Artavanis-Tsakonas S, Delidakis C, Fehon RG. The Notch locus and the cell biology of neuroblast segregation.Annu Rev Cell Biol. 1991;7:427–452.CrossRefPubMedGoogle Scholar
  31. 31.
    Xu T, Rebay I, Fleming RJ, Scottgale TN, Artavanis-Tsakonas S. The Notch locus and the genetic circuitry involved in earlyDrosophila neurogenesis.Genes Dev. 1990;4:464–475.CrossRefPubMedGoogle Scholar
  32. 32.
    Coffman CR, Skoglund P, Harris WA, Kintner CR. Expression of an extracellular deletion of Xotch diverts cell fate inXenopus embryos.Cell. 1993;73:659–671.CrossRefPubMedGoogle Scholar
  33. 33.
    Chitnis A, Henrique D, Lewis J, Ish-Horowicz D, Kintner C. Primary neurogenesis inXenopus embryos regulated by a homologue of theDrosophila neurogenic geneDelta.Nature. 1995;375:761–766.CrossRefPubMedGoogle Scholar
  34. 34.
    de la Pompa JL, Wakeham A, Correia KM, et al. Conservation of the Notch signalling pathway in mammalian neurogenesis.Development. 1997;124:1139–1148.PubMedGoogle Scholar
  35. 35.
    Lutolf S, Radtke F, Aguet M, Suter U, Taylor V. Notch1 is required for neuronal and glial differentiation in the cerebellum.Development. 2002;129:373–385.PubMedGoogle Scholar
  36. 36.
    Yoon K, Nery S, Rutlin ML, et al. Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors.J Neurosci. 2004;24:9497–9506.CrossRefPubMedGoogle Scholar
  37. 37.
    Fre S, Huyghe M, Mourikis P, et al. Notch signals control the fate of immature progenitor cells in the intestine.Nature. 2005;435:964–968.CrossRefPubMedGoogle Scholar
  38. 38.
    van Es JH, van Gijn ME, Riccio O, et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.Nature. 2005;435:959–963.CrossRefPubMedGoogle Scholar
  39. 39.
    Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.J Biol Chem. 2004;279:12876–12882.CrossRefPubMedGoogle Scholar
  40. 40.
    Milano J, McKay J, Dagenais C, et al. Modulation of Notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.Toxicol Sci. 2004;82:341–358.CrossRefPubMedGoogle Scholar
  41. 41.
    Kumano K, Chiba S, Kunisato A, et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.Immunity. 2003;18:699–711.CrossRefPubMedGoogle Scholar
  42. 42.
    Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A. RBPjk-dependent Notch function regulatesGata2 and is essential for the formation of intra-embryonic hematopoietic cells.Development. 2005;132:1117–1126.CrossRefPubMedGoogle Scholar
  43. 43.
    de Bruijn MF, Ma X, Robin C, et al. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta.Immunity. 2002;16:673–683.CrossRefPubMedGoogle Scholar
  44. 44.
    Calvi L, Adams G, Weibrecht K, et al. Osteoblastic cells regulate the haematopoietic stem cell niche.Nature. 2003;425:841–846.CrossRefPubMedGoogle Scholar
  45. 45.
    Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.Blood. 2002;99:2369–2378.CrossRefPubMedGoogle Scholar
  46. 46.
    Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling.Nat Med. 2000;6:1278–1281.CrossRefPubMedGoogle Scholar
  47. 47.
    Varnum-Finney B, Purton LE, Yu M, et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells.Blood. 1998;91:4084–4091.PubMedGoogle Scholar
  48. 48.
    Carlesso N, Aster JC, Sklar J, Scadden DT. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics.Blood. 1999;93:838–848.PubMedGoogle Scholar
  49. 49.
    Karanu FN, Murdoch B, Gallacher L, et al. The Notch ligand Jagged-1 represents a novel growth factor of human hematopoietic stem cells.J Exp Med. 2000;192:1365–1372.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Karanu FN, Murdoch B, Miyabayashi T, et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells.Blood. 2001;97:1960–1967.CrossRefPubMedGoogle Scholar
  51. 51.
    Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34+CD38- cord blood cells.J Clin Invest. 2002;110:1165–1174.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Varnum-Finney B, Brashem-Stein C, Bernstein ID. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability.Blood. 2003;101:1784–1789.CrossRefPubMedGoogle Scholar
  53. 53.
    Karanu FN, Yuefei L, Gallacher L, Sakano S, Bhatia M. Differential response of primitive human CD34- and CD34+ hematopoietic cells to the Notch ligand Jagged-1.Leukemia. 2003;17:1366–1374.CrossRefPubMedGoogle Scholar
  54. 54.
    Duncan AW, Rattis FM, DiMascio LN, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.Nat Immunol. 2005;6:314–322.CrossRefPubMedGoogle Scholar
  55. 55.
    Han H, Tanigaki K, Yamamoto N, et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.Int Immunol. 2002;14:637–645.CrossRefPubMedGoogle Scholar
  56. 56.
    Radtke F, Wilson A, Stark G, et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1.Immunity. 1999;10:547–558.CrossRefPubMedGoogle Scholar
  57. 57.
    Saito T, Chiba S, Ichikawa M, et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development.Immunity. 2003;18:675–685.CrossRefPubMedGoogle Scholar
  58. 58.
    Mancini SJ, Mantei N, Dumortier A, et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation.Blood. 2005;105:2340–2342.CrossRefPubMedGoogle Scholar
  59. 59.
    Jan YN, Jan LY. Genetic control of cell fate specification inDrosophila peripheral nervous system.Annu Rev Genet. 1994;28:373–393.CrossRefPubMedGoogle Scholar
  60. 60.
    Morrison S J, Perez SE, Qiao Z, et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells.Cell. 2000;101:499–510.CrossRefPubMedGoogle Scholar
  61. 61.
    Zine A, Van De Water TR, de Ribaupierre F. Notch signaling regulates the pattern of auditory hair cell differentiation in mammals.Development. 2000;127:3373–3383.PubMedGoogle Scholar
  62. 62.
    Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine.Science. 2001;294:2155–2158.CrossRefPubMedGoogle Scholar
  63. 63.
    Pardanaud L, Yassine F, Dieterlen-Lievre F. Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny.Development. 1989;105:473–485.PubMedGoogle Scholar
  64. 64.
    Pui JC, Allman D, Xu L, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination.Immunity. 1999;11:299–308.CrossRefPubMedGoogle Scholar
  65. 65.
    Wilson A, MacDonald HR, Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.J Exp Med. 2001;194:1003–1012.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Koch U, Lacombe TA, Holland D, et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.Immunity. 2001;15:225–236.CrossRefPubMedGoogle Scholar
  67. 67.
    Hozumi K, Negishi N, Suzuki D, et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo.Nat Immunol. 2004;5:638–644.CrossRefPubMedGoogle Scholar
  68. 68.
    Tanigaki K, Han H, Yamamoto N, et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells.Nat Immunol. 2002;3:443–450.CrossRefPubMedGoogle Scholar
  69. 69.
    Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters.Curr Biol. 2000;10:491–500.CrossRefPubMedGoogle Scholar
  70. 70.
    Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin.Nat Genet. 2003;33:416–421.CrossRefPubMedGoogle Scholar
  71. 71.
    Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke E. Inactivation ofNotch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ lineage thymocytes.Immunity. 2002;16:869–879.CrossRefPubMedGoogle Scholar
  72. 72.
    Hoflinger S, Kesavan K, Fuxa M, et al. Analysis of Notch1 function by in vitro T cell differentiation ofPax5 mutant lymphoid progenitors.J Immunol. 2004;173:3935–3944.CrossRefPubMedGoogle Scholar
  73. 73.
    Gallahan D, Callahan R. Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors.J Virol. 1987;61:66–74.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene.Development. 1996;122:2251–2259.PubMedGoogle Scholar
  75. 75.
    Jhappan C, Gallahan D, Stahle C, et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.Genes Dev. 1992;6:345–355.CrossRefPubMedGoogle Scholar
  76. 76.
    Gallahan D, Jhappan C, Robinson G, et al. Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis.Cancer Res. 1996;56:1775–1785.PubMedGoogle Scholar
  77. 77.
    Girard L, Hanna Z, Beaulieu N, et al. Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis.Genes Dev. 1996;10:1930–1944.CrossRefPubMedGoogle Scholar
  78. 78.
    Rohn JL, Lauring AS, Linenberger ML, Overbaugh J. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma.J Virol. 1996;70:8071–8080.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of theDrosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.Cell. 1991;66:649–661.CrossRefPubMedGoogle Scholar
  80. 80.
    Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.J Exp Med. 1996;183:2283–2291.CrossRefPubMedGoogle Scholar
  81. 81.
    Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.Science. 2004;306:269–271.CrossRefPubMedGoogle Scholar
  82. 82.
    Jundt F, Anagnostopoulos I, Forster R, et al. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma.Blood. 2002;99:3398–3403.CrossRefPubMedGoogle Scholar
  83. 83.
    Hubmann R, Schwarzmeier JD, Shehata M, et al. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.Blood. 2002;99:3742–3747.CrossRefPubMedGoogle Scholar
  84. 84.
    Hendrix MJ, Seftor RE, Seftor EA, et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination.Cancer Res. 2002;62:665–668.PubMedGoogle Scholar
  85. 85.
    Qin JZ, Stennett L, Bacon P, et al. p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas.Mol Cancer Ther. 2004;3:895–902.PubMedGoogle Scholar
  86. 86.
    Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix.Proc NatlAcad Sci USA. 1995;92:6414–6418.CrossRefGoogle Scholar
  87. 87.
    Daniel B, Rangarajan A, Mukherjee G, Vallikad E, Krishna S. The link between integration and expression of human papillomavirus type 16 genomes and cellular changes in the evolution of cervical intraepithelial neoplastic lesions.J Gen Virol. 1997;78(pt 5):1095–1101.CrossRefPubMedGoogle Scholar
  88. 88.
    Weijzen S, Rizzo P, Braid M, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.Nat Med. 2002;8:979–986.CrossRefPubMedGoogle Scholar
  89. 89.
    Dang TP, Gazdar AF, Virmani AK, et al. Chromosome 19 translocation, overexpression of Notch3, and human lung cancer.J Natl Cancer Inst. 2000;92:1355–1357.CrossRefPubMedGoogle Scholar
  90. 90.
    Rae FK, Stephenson SA, Nicol DL, Clements JA. Novel association of a diverse range of genes with renal cell carcinoma as identified by differential display.IntJ Cancer. 2000;88:726–732.CrossRefGoogle Scholar
  91. 91.
    Suzuki T, Aoki D, Susumu N, Udagawa Y, Nozawa S. Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.Int J Oncol. 2000;17:1131–1139.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2005

Authors and Affiliations

  • Alexis Dumortier
    • 1
  • Anne Wilson
    • 1
  • H. Robson MacDonald
    • 1
  • Freddy Radtke
    • 1
  1. 1.Ludwig Institute for Cancer ResearchLausanne Branch, University of Lausanne1066 EpalingesSwitzerland

Personalised recommendations