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Notch regulation of lymphocyte development and function

Abstract

Notch proteins regulate a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal development. Mammals have four Notch receptors that bind five different ligands. The function of Notch signaling during lymphopoiesis and T cell neoplasia, based on gain-of-function and conditional loss-of-function approaches for the Notch1 receptor, indicates Notch1 is essential in T cell lineage commitment. Recent studies have addressed the involvement of other Notch receptors and ligands as well as their downstream targets, demonstrating additional functions of Notch signaling in embryonic hematopoiesis, intrathymic T cell development, B cell development and peripheral T cell function.

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Figure 1: Notch receptors and signaling.
Figure 2: Notch receptor-ligand expression during hematopoiesis in the mouse.
Figure 3: Notch signaling in lymphopoiesis.

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References

  1. Morgan, T.H. The theory of the gene. Am. Nat. 51, 513–544 (1917).

    Article  Google Scholar 

  2. Wharton, K.A., Johansen, K.M., 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 43, 567–581 (1985).

    Article  CAS  PubMed  Google Scholar 

  3. Kidd, S., Kelley, M.R. & Young, M.W. Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol. Cell. Biol. 6, 3094–30108 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Artavanis-Tsakonas, S., Rand, M.D. & Lake, R.J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Greenwald, I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev. 12, 1751–1762 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Davis, R.L. & Turner, D.L. Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene 20, 8342–8357 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Krebs, L.T., Deftos, M.L., Bevan, M.J. & Gridley, T. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Dev. Biol. 238, 110–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Deftos, M.L., Huang, E., Ojala, E.W., Forbush, K.A. & Bevan, M.J. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13, 73–84 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reizis, B. & Leder, P. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev. 16, 295–300 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okajima, T. & Irvine, K.D. Regulation of notch signaling by o-linked fucose. Cell 111, 893–904 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Okajima, T., Xu, A. & Irvine, K.D. Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe. J. Biol. Chem. 278, 42340–42345 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Haines, N. & Irvine, K. Glycosylation regulates Notch signalling. Nat. Rev. Mol. Cell Biol. 4, 786–797 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Haltiwanger, R.S. & Stanley, P. Modulation of receptor signaling by glycosylation: fringe is an O-fucose-β1,3-N-acetylglucosaminyltransferase. Biochim. Biophys. Acta 1573, 328–335 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Matsuno, K., Diederich, R.J., Go, M.J., Blaumueller, C.M. & Artavanis-Tsakonas, S. Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development 121, 2633–2644 (1995).

    CAS  PubMed  Google Scholar 

  17. Frise, E., Knoblich, J.A., Younger-Shepherd, S., Jan, L.Y. & Jan, Y.N. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc. Natl. Acad. Sci. USA 93, 11925–11932 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yun, T.J. & Bevan, M.J. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J. Immunol. 170, 5834–5841 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Kuroda, K. et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18, 301–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Oswald, F. et al. SHARP is a novel component of the Notch/RBP-Jκ signalling pathway. Embo J. 21, 5417–5426 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Reynolds, T.C., Smith, S.D. & Sklar, J. Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the β T cell receptor gene in human lymphoblastic neoplasms. Cell 50, 107–117 (1987).

    Article  CAS  PubMed  Google Scholar 

  22. Ellisen, L.W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Pear, W.S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Robey, E. et al. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87, 483–492 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Bellavia, D. et al. Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J. 19, 3337–3348 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dorsch, M. et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood 100, 2046–2055 (2002).

    CAS  PubMed  Google Scholar 

  27. Yan, X.Q. et al. A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 98, 3793–3799 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Allman, D. et al. Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J. Exp. Med. 194, 99–106 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bellavia, D. et al. Combined expression of pTα and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc. Natl. Acad. Sci. USA 99, 3788–3793 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weng, A.P. et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol. Cell Biol. 23, 655–664 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Girard, L. 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. 10, 1930–1944 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Rohn, J.L., Lauring, A.S., Linenberger, M.L. & Overbaugh, J. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J. Virol. 70, 8071–8080 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lauring, A.S. & Overbaugh, J. Evidence that an IRES within the Notch2 coding region can direct expression of a nuclear form of the protein. Mol. Cell 6, 939–945 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Feldman, B.J., Hampton, T. & Cleary, M.L. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Blood 96, 1906–1913 (2000).

    CAS  PubMed  Google Scholar 

  35. Beverly, L.J. & Capobianco, A.J. Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell 3, 551–564 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Talora, C. et al. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity. EMBO Rep. 4, 1067–1072 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jundt, F. et al. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99, 3398–3403 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Hubmann, R. et al. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood 99, 3742–3747 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Godin, I. & Cumano, A. The hare and the tortoise: an embryonic haematopoietic race. Nat. Rev. Immunol. 2, 593–5604 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Pardanaud, L., Yassine, F. & Dieterlen-Lievre, F. Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny. Development 105, 473–485 (1989).

    CAS  PubMed  Google Scholar 

  41. Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J.C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998).

    CAS  PubMed  Google Scholar 

  42. de Bruijn, M.F. et al. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity 16, 673–683 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Kumano, K. et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18, 699–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Calvi, L. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Stier, S., Cheng, T., Dombkowski, D., Carlesso, N. & Scadden, D.T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99, 2369–2378 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Varnum-Finney, B. et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat. Med. 6, 1278–1281 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Karanu, F.N. et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J. Exp. Med. 192, 1365–1372 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Karanu, F.N., 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 17, 1366–1374 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Varnum-Finney, B. et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91, 4084–4091 (1998).

    CAS  PubMed  Google Scholar 

  50. Ohishi, K., Varnum-Finney, B. & Bernstein, I.D. Delta-1 enhances marrow and thymus repopulating ability of human CD34+CD38 cord blood cells. J. Clin. Invest. 110, 1165–1174 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Karanu, F.N. et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 97, 1960–1967 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Varnum-Finney, B., Brashem-Stein, C. & Bernstein, I.D. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood 101, 1784–1789 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Carlesso, N., Aster, J.C., Sklar, J. & Scadden, D.T. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood 93, 838–848 (1999).

    CAS  PubMed  Google Scholar 

  54. Kunisato, A. et al. HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood 101, 1777–1783 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Han, H. 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. 14, 637–645 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Milner, L.A. & Bigas, A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood 93, 2431–2448 (1999).

    CAS  PubMed  Google Scholar 

  59. Ohishi, K., Katayama, N., Shiku, H., Varnum-Finney, B. & Bernstein, I. Notch signalling in hematopoiesis. Semin. Cell Dev. Biol. 2, 143–150 (2003).

    Article  CAS  Google Scholar 

  60. Wilson, A., Ferrero, I., MacDonald, H.R. & Radtke, F. Cutting edge: An essential role for notch-1 in the development of both thymus-independent and -dependent T cells in the gut. J. Immunol. 165, 5397–5400 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Wilson, A., MacDonald, H.R. & Radtke, F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003–1012 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Krebs, L. et al. Characterization of Notch3-deficient mice: Normal embryonic development. Genesis 3, 139–143 (2003).

    Article  CAS  Google Scholar 

  63. Pui, J.C. et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Kawamata, S., Du, C., Li, K. & Lavau, C. Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations. Oncogene 21, 3855–3863 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Souabni, A., Cobaleda, C., Schebesta, M. & Busslinger, M. Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Immunity 17, 781–793 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Cotta, C.V., Zhang, Z., Kim, H.G. & Klug, C.A. Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development. Blood 101, 4342–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Koch, U. et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 15, 225–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Izon, D.J. et al. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16, 231–243 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. French, M.B. et al. Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification. J. Immunol. 168, 3173–3180 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Harman, B.C., Jenkinson, E.J. & Anderson, G. Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors. J. Immunol. 170, 1299–1303 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. Jaleco, A.C. et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194, 991–1002 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Schmitt, T.M. & Zuniga-Pflucker, J.C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. MacDonald, H.R., Radtke, F. & Wilson, A. T cell fate specification and αβ/γδ lineage commitment. Curr. Op. Immunol. 13, 219–224 (2001).

    Article  CAS  Google Scholar 

  75. Washburn, T. et al. Notch activity influences the αβ versus γδ T cell lineage decision. Cell 88, 833–843 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Wolfer, A., Wilson, A., Nemir, M., MacDonald, H.R. & Radtke, F. Inactivation of Notch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ lineage thymocytes. Immunity 16, 869–879 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Kang, J., Volkmann, A. & Raulet, D.H. Evidence that γδ versus αβ T cell fate determination is initiated independently of T cell receptor signaling. J. Exp. Med. 193, 689–698 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Newton, K., Harris, A.W. & Strasser, A. FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. EMBO J. 19, 931–941 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fowlkes, B.J. & Robey, E.A. A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development. J. Immunol. 169, 1817–1821 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Wolfer, A. et al. Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8 T cell development. Nat. Immunol. 2, 235–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Hoyne, G.F. et al. Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4+ T cells. Int. Immunol. 12, 177–185 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Yvon, E.S. et al. Over expression of the Notch ligand, Jagged-1 induces alloantigen-specific human regulatory T cells. Blood 102, 3815–3821 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Vigouroux, S. et al. Induction of antigen-specific regulatory T cells following overexpression of a Notch ligand by human B lymphocytes. J. Virol. 77, 10872–10880 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Anastasi, E. et al. Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes. J. Immunol. 171, 4504–4511 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Maekawa, Y. et al. Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity 19, 549–559 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Wong, K. et al. Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism. J. Clin. Inv. 112, 1741–1750 (2003).

    Article  CAS  Google Scholar 

  88. Adler, S.H. et al. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J. Immunol. 171, 2896–2903 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Palaga, T., Miele, L., Golde, T.E. & Osborne, B.A. TCR-mediated notch signaling regulates proliferation and IFN-γ production in peripheral T cells. J. Immunol. 171, 3019–3024 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Radtke, F., Wilson, A., Ernst, B. & MacDonald, H.R. The role of Notch signaling during hematopoietic lineage commitment. Immunol. Rev. 187, 65–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Tanigaki, K. et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat. Immunol. 3, 443–450 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Huang, E.Y., Gallegos, A.M., Richards, S.M., Lehar, S.M. & Bevan, M.J. Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition. J. Immunol. 171, 2296–2304 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Hozumi, K., Abe, N., Chiba, S., Hirai, H. & Habu, S. Active form of Notch members can enforce T lymphopoiesis on lymphoid progenitors in the monolayer culture specific for B cell development. J. Immunol. 170, 4973–4979 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Hu, Q. et al. F3/contactin acts as a functional ligand for Notch during oligodendrocyte. Cell 2003 115, 163–175 (2003).

    CAS  Google Scholar 

  95. Parks, A.L., Klueg, K.M., Stout, J.R. & Muskavitch, M.A. Ligand endocytosis drives receptor dissociation and activation in the Notch pathway. Development 127, 1373–1385 (2000).

    CAS  PubMed  Google Scholar 

  96. Kao, H. et al. A histone deacetylase corepressor complex regulates the Notch signal. Genes Dev. 1998 15, 2269–2277 (1998).

    Google Scholar 

  97. Hsieh, J.J., Zhou, S., Chen, L., Young, D.B. & Hayward, S.D. CIR, a corepressor linking the DNA binding factor CBF1 to the histone. Proc. Natl. Acad. Sci. USA 96, 23–28 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhou, S. et al. SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain CIR, a corepressor linking the DNA binding factor CBF1 to the histone. Mol. Cell Biol. 20, 2400–2410 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jeffries, S., Robbins, D.J. & Capobianco, A.J. Characterization of a high-molecular-weight Notch complex in the nucleus. Mol. Cell Biol. 11, 3927–3941 (2002).

    Article  CAS  Google Scholar 

  100. Wu, L. et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional. Nat. Genet. 4, 484–489 (2000).

    Article  CAS  Google Scholar 

  101. Jones, P. et al. Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 92, 1505–1511 (1998).

    CAS  PubMed  Google Scholar 

  102. Han, W., Ye, Q. & Moore, M.A. A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells. Blood 95, 1616–1625 (2000).

    CAS  PubMed  Google Scholar 

  103. Tsai, S., Fero, J. & Bartelmez, S. Mouse Jagged2 is differentially expressed in hematopoietic progenitors and endothelial cells and promotes the survival and proliferation of hematopoietic progenitors by direct cell-to-cell contact. Blood 96, 950–957 (2000).

    CAS  PubMed  Google Scholar 

  104. Singh, N., Phillips, R.A., Iscove, N.N. & Egan, S.E. Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis. Exp. Hematol. 28, 527–534 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Jonsson, J.I., Xiang, Z., Pettersson, M., Lardelli, M. & Nilsson, G. Distinct and regulated expression of Notch receptors in hematopoietic lineages and during myeloid differentiation. Eur. J. Immunol. 31, 3240–3247 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Walker, L., Carlson, A., Tan-Pertel, H.T., Weinmaster, G. & Gasson, J. The notch receptor and its ligands are selectively expressed during hematopoietic development in the mouse. Stem Cells 19, 543–552 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Yamaguchi, E. et al. Expression of Notch ligands, Jagged1, 2 and Delta1 in antigen presenting cells in mice. Immunol. Lett. 81, 59–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Weijzen, S. et al. The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells. J. Immunol. 169, 4273–4278 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Anderson, G., Pongracz, J., Parnell, S. & Jenkinson, E.J. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur. J. Immunol. 31, 3349–3354 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Hasserjian, R.P., Aster, J.C., Davi, F., Weinberg, D.S. & Sklar, J. Modulated expression of notch1 during thymocyte development. Blood 88, 970–976 (1996).

    CAS  PubMed  Google Scholar 

  111. Felli, M.P. et al. Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int. Immunol. 11, 1017–1025 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Kaneta, M. et al. A role for pref-1 and HES-1 in thymocyte development. J. Immunol. 164, 256–264 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all our colleagues who shared unpublished results with us and apologize to those whose work was not cited because of space limitations. F.R. and S.M. are supported in part by grants from the Swiss Cancer League, the Swiss National Science Foundation, the Leenaards Foundation, the EMBO Young Investigator Program and the Roche Foundation.

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Radtke, F., Wilson, A., Mancini, S. et al. Notch regulation of lymphocyte development and function. Nat Immunol 5, 247–253 (2004). https://doi.org/10.1038/ni1045

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