Thymus Organogenesis and Development of the Thymic Stroma

  • Craig S. Nowell
  • Alison M. Farley
  • C. Clare Blackburn
Part of the Methods in Molecular Biology™ book series (MIMB, volume 380)


T-cell development occurs principally in the thymus. Here, immature progenitor cells are guided through the differentiation and selection steps required to generate a complex T-cell repertoire that is both self-tolerant and has propensity to bind self major histocompatibility complex. These processes depend on an array of functionally distinct epithelial cell types within the thymic stroma, which have a common developmental origin in the pharyngeal endoderm. Here, we describe the structural and phenotypic attributes of the thymic stroma, and review current cellular and molecular understanding of thymus organogenesis.

Key Words

Thymus endoderm thymic epithelium epithelium organogenesis patterning stem cell progenitor cell Foxn1 


  1. 1.
    Boyd, R. L., Tucek, C. L., Godfrey, D. L, et al. (1993) The thymic microenvironment. Immunol. Today 14, 445–459.PubMedCrossRefGoogle Scholar
  2. 2.
    van Ewijk, W., Shores, E. W., and Singer, A. (1994) Crosstalk in the mouse thymus. Immunol. Today 15, 214–217.PubMedCrossRefGoogle Scholar
  3. 3.
    Van Vliet, E., Jenkinson, E. J., Kingston, R., Owen, J. J., and Van Ewijk, W. (1985) Stromal cell types in the developing thymus of the normal and nude mouse embryo. Eur. J. Immunol. 15, 675–681.PubMedCrossRefGoogle Scholar
  4. 4.
    Lind, E. F., Prockop, S. E., Porritt, H. E., and Petrie, H. T. (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194, 127–134.PubMedCrossRefGoogle Scholar
  5. 5.
    van de Wijngaert, F. P., Rademakers, L. H., Schuurman, H. J., de Weger, R. A., and Kater, L. (1983) Identification and in situ localization of the “thymic nurse cell” in man. J. Immunol. 130, 2348–2351.PubMedGoogle Scholar
  6. 6.
    Brekelmans, P. and van Ewijk, W. (1990) Phenotypic characterization of murine thymic microenvironments. Semin. Immunol. 2, 13–24.PubMedGoogle Scholar
  7. 7.
    Boyd, R. L., Wilson, T. J., Bean, A. G., Ward, H. A., and Gershwin, M. E. (1992) Phenotypic characterization of chicken thymic stromal elements. Dev. Immunol. 2, 51–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Godfrey, D. L, Izon, D. J., Tucek, C. L., Wilson, T. J., and Boyd, R. L. (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunol. 70, 66–74.Google Scholar
  9. 9.
    van de Wijngaert, F. P., Kendall, M. D., Schuurman, H. J., Rademakers, L. H., and Kater, L. (1984) Heterogeneity of epithelial cells in the human thymus. An ultrastructural study. Cell Tissue Res. 237, 227–237.PubMedCrossRefGoogle Scholar
  10. 10.
    Wekerle, H. and Ketelsen, U. P. (1980) Thymic nurse cells-Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283, 402–404.PubMedCrossRefGoogle Scholar
  11. 11.
    Wekerle, H., Ketelsen, U. P., and Ernst, M. (1980) Thymic nurse cells. Lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization. J. Exp. Med. 151, 925–944.PubMedCrossRefGoogle Scholar
  12. 12.
    von Gaudecker, B., Steinmann, G. G., Hansmann, M. L., Harpprecht, J., Milicevic, N. M., and Muller-Hermelink, H. K. (1986) Immunohistochemical characterization of the thymic microenvironment. A light-microscopic and ultrastructural immunocytochemical study. Cell Tissue Res. 244, 403–412.CrossRefGoogle Scholar
  13. 13.
    Bofill, M., Janossy, G., Willcox, N., Chilosi, M., Trejdosiewicz, L. K., and Newsom-Davis, J. (1985) Microenvironments in the normal thymus and the thymus in myasthenia gravis. Am. J. Pathol. 119, 462–473.PubMedGoogle Scholar
  14. 14.
    Surh, C. D., Gao, E. K., Kosaka, H., et al. (1992) Two subsets of epithelial cells in the thymic medulla. J. Exp. Med. 176, 495–505.PubMedCrossRefGoogle Scholar
  15. 15.
    Farr, A. G. and Nakane, P. K. (1983) Cells bearing Ia antigens in the murine thymus. An ultrastructural study. Am. J. Pathol. 111, 88–97.PubMedGoogle Scholar
  16. 16.
    Jenkinson, E. J., Van Ewijk, W., and Owen, J. J. (1981) Major histocompatibility complex antigen expression on the epithelium of the developing thymus in normal and nude mice. J. Exp. Med. 153, 280–292.PubMedCrossRefGoogle Scholar
  17. 17.
    Klug, D. B., Carter, C., Crouch, E., Roop, D., Conti, C. J., and Richie, E. R. (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl. Acad. Sci. USA 95, 11,822–11,827.PubMedCrossRefGoogle Scholar
  18. 18.
    Duijvestijn, A. M. and Hoefsmit, E. C. (1981) Ultrastructure of the rat thymus: the micro-environment of T-lymphocyte maturation. Cell Tissue Res. 218, 279–292.PubMedCrossRefGoogle Scholar
  19. 19.
    Milicevic, N. M., Milicevic, Z., Colic, M., and Mujovic, S. (1987) Ultrastructural study of macrophages in the rat thymus, with special reference to the corticomedullary zone. J. Anat. 150, 89–98.PubMedGoogle Scholar
  20. 20.
    Cardarelli, P. M., Crispe, I. N., and Pierschbacher, M. D. (1988) Preferential expression of fibronectin receptors on immature thymocytes. J. Cell Biol. 106, 2183–2190.PubMedCrossRefGoogle Scholar
  21. 21.
    Cardarelli, P. M. and Pierschbacher, M. D. (1986) T-lymphocyte differentiation and the extracellular matrix: identification of a thymocyte subset that attaches specifically to fibronectin. Proc. Natl. Acad. Sci. USA 83, 2647–2651.PubMedCrossRefGoogle Scholar
  22. 22.
    Schreiber, L., Eshel, I., Meilin, A., Sharabi, Y., and Shoham, J. (1991) Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. III. Growth conditions of human thymic epithelial cells and immunomodulatory activities in their culture supernatant. Immunol. 74, 621–629.Google Scholar
  23. 23.
    Watt, S. M., Thomas, J. A., Murdoch, S. J., Kearney, L., Chang, S. E., and Bartek, J. (1991) Human thymic epithelial cells are frequently transformed by retro viral vectors encoding simian virus 40. Cell. Immunol. 138, 456–472.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson, G., Anderson, K. L., Tchilian, E. Z., Owen, J. J., and Jenkinson, E. J. (1997) Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules. Eur. J. Immunol. 27, 1200–1206.PubMedCrossRefGoogle Scholar
  25. 25.
    Boyd, R. L. and Hugo, P. (1991) Towards an integrated view of thymopoiesis. Immunol. Today 12, 71–79.PubMedCrossRefGoogle Scholar
  26. 26.
    Savino, W., Villa-Verde, D. M. and Lannes-Vieira, J. (1993) Extracellular matrix proteins in intrathymic T-cell migration and differentiation? Immunol. Today 14, 158–161.PubMedCrossRefGoogle Scholar
  27. 27.
    Watt, S. M., Thomas, J. A., Edwards, A. J., Murdoch, S. J., and Horton, M. A. (1992) Adhesion receptors are differentially expressed on developing thymocytes and epithelium in human thymus. Exp. Hematol. 20, 1101–1111.PubMedGoogle Scholar
  28. 28.
    Plotkin, J., Prockop, S. E., Lepique, A., and Petrie, H. T. (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171, 4521–4527.PubMedGoogle Scholar
  29. 29.
    Anderson, G., Owen, J. J., Moore, N. C., and Jenkinson, E. J. (1994) Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro. J. Exp. Med. 179, 2027–2031.PubMedCrossRefGoogle Scholar
  30. 30.
    Ge, Q. and Chen, W. F. (2000) Effect of murine thymic epithelial cell line (MTEC1) on the functional expression of CD4(+)CD8(−) thymocyte subgroups. Int. Immunol. 12, 1127–1133.PubMedCrossRefGoogle Scholar
  31. 31.
    Moore, N. C., Anderson, G., Smith, C. A., Owen, J. J., and Jenkinson, E. J. (1993) Analysis of cytokine gene expression in subpopulations of freshly isolated thymocytes and thymic stromal cells using semiquantitative polymerase chain reaction. Eur. J. Immunol. 23, 922–927.PubMedCrossRefGoogle Scholar
  32. 32.
    Hare, K. J., Jenkinson, E. J., and Anderson, G. (2000) An essential role for the IL-7 receptor during intrathymic expansion of the positively selected neonatal T cell repertoire. J. Immunol. 165, 2410–2414.PubMedGoogle Scholar
  33. 33.
    Zamisch, M., Moore-Scott, B., Su, D. M., Lucas, P. J., Manley, N., and Richie, E. R. (2005) Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J. Immunol. 17 4, 60–67.Google Scholar
  34. 34.
    von Freeden-Jeffry, U., Vieira, P., Lucian, L. A., McNeil, T., Burdach, S. E., and Murray, R. (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526.CrossRefGoogle Scholar
  35. 35.
    Crompton, T., Outram, S. V., Buckland, J., and Owen, M. J. (1998) Distinct roles of the interleukin-7 receptor alpha chain in fetal and adult thymocyte development revealed by analysis of interleukin-7 receptor alpha-deficient mice. Eur. J. Immunol. 28, 1859–1866.PubMedCrossRefGoogle Scholar
  36. 36.
    Zuniga-Pflucker, J. C., Di, J., and Lenardo, M. J. (1995) Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation. Science 268, 1906–1909.PubMedCrossRefGoogle Scholar
  37. 37.
    Savino, W., Mendes-da-Cruz, D. A., Silva, J. S., Dardenne, M., and Cotta-de-Almeida, V. (2002) Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines? Trends Immunol. 23, 305–313.PubMedCrossRefGoogle Scholar
  38. 38.
    Misslitz, A., Pabst, O., Hintzen, G., Ohl, L., Kremmer, E., Petrie, H. T., and Forster, R. (2004) Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491.PubMedCrossRefGoogle Scholar
  39. 39.
    Benz, C., Heinzel, K., and Bleul, C. C. (2004) Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34, 3652–3663.PubMedCrossRefGoogle Scholar
  40. 40.
    Cosgrove, D., Chan, S. H., Waltzinger, C., Benoist, C., and Mathis, D. (1992) The thymic compartment responsible for positive selection of CD4+ T cells. Int. Immunol. 4, 707–710.PubMedCrossRefGoogle Scholar
  41. 41.
    Benoist, C. and Mathis, D. (1989) Positive selection of the T cell repertoire: where and when does it occur? Cell 58, 1027–1033.PubMedCrossRefGoogle Scholar
  42. 42.
    Berg, L. J., Pullen, A. M., Fazekas de St. Groth, B., Mathis, D., Benoist, C., and Davis, M. M. (1989) Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell 58, 1035–1046.PubMedCrossRefGoogle Scholar
  43. 43.
    Wilson, A., MacDonald, H. R., and Radtke, F. (2001) Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003–1012.PubMedCrossRefGoogle Scholar
  44. 44.
    Radtke, F., Wilson, A., Stark, G., et al. (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558.PubMedCrossRefGoogle Scholar
  45. 45.
    Harman, B. C., Jenkinson, E. J., and Anderson, G. (2003) Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors. J. Immunol. 170, 1299–1303.PubMedGoogle Scholar
  46. 46.
    Anderson, G., Pongracz, J., Parnell, S., and Jenkinson, E. J. (2001) 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Allman, D., Karnell, F. G., Punt, J. A., et al. (2001) Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J. Exp. Med. 194, 99–106.PubMedCrossRefGoogle Scholar
  48. 48.
    Huang, E. Y., Gallegos, A. M., Richards, S. M., Lehar, S. M., and Bevan, M. J. (2003) Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition. J. Immunol. 171, 2296–2304.PubMedGoogle Scholar
  49. 49.
    Deftos, M. L., Huang, E., Ojala, E. W., Forbush, K. A., and Bevan, M. J. (2000) Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13, 73–84.PubMedCrossRefGoogle Scholar
  50. 50.
    Deftos, M. L., He, Y. W., Ojala, E. W., and Bevan, M. J. (1998) Correlating notch signaling with thymocyte maturation. Immunity 9, 777–786.PubMedCrossRefGoogle Scholar
  51. 51.
    Kyewski, B., Derbinski, J., Gotter, J., and Klein, L. (2002) Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 23, 364–371.PubMedCrossRefGoogle Scholar
  52. 52.
    Gotter, J., Brors, B., Hergenhahn, M., and Kyewski, B. (2004) Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166.PubMedCrossRefGoogle Scholar
  53. 53.
    Boehm, T., Scheu, S., Pfeffer, K., and Bleul, C. C. (2003) Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J. Exp. Med. 198, 757–769.PubMedCrossRefGoogle Scholar
  54. 54.
    Anderson, M. S., Venanzi, E. S., Klein, L., et al. (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401.PubMedCrossRefGoogle Scholar
  55. 55.
    Chin, R. K., Lo, J. C., Kim, O., et al. (2003) Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4, 1121–1127.PubMedCrossRefGoogle Scholar
  56. 56.
    Gotter, J. and Kyewski, B. (2004) Regulating self-tolerance by deregulating gene expression. Curr. Opin. Immunol. 16, 741–745.PubMedCrossRefGoogle Scholar
  57. 57.
    Liston, A., Lesage, S., Wilson, J., Peltonen, L., and Goodnow, C. C. (2003) Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354.PubMedCrossRefGoogle Scholar
  58. 58.
    Villasenor, J., Benoist, C., and Mathis, D. (2005) AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204, 156–164.PubMedCrossRefGoogle Scholar
  59. 59.
    Vogel, A., Liermann, H., Harms, A., Strassburg, C. P., Manns, M. P., and Obermayer-Straub, P. (2001) Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune poly glandular syndrome type 1. Hepatol. 33, 1047–1052.CrossRefGoogle Scholar
  60. 60.
    Le Lievre, C. S. and Le Douarin, N. M. (1975) Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryol. Exp. Morphol. 34, 125–154.PubMedGoogle Scholar
  61. 61.
    Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P., and Sucov, H. M. (2000) Fate of the mammalian cardiac neural crest. Development 127, 1607–1616.PubMedGoogle Scholar
  62. 62.
    Owen, J. J. and Ritter, M. A. (1969) Tissue interaction in the development of thymus lymphocytes. J. Exp. Med. 129, 431–442.PubMedCrossRefGoogle Scholar
  63. 63.
    Cordier, A. C. and Haumont, S. M. (1980) Development of thymus, parathyroids, and ultimo-branchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–263.PubMedCrossRefGoogle Scholar
  64. 64.
    Jotereau, F., Heuze, F., Salomon-Vie, V., and Gascan, H. (1987) Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J. Immunol. 138, 1026–1030.PubMedGoogle Scholar
  65. 65.
    Douagi, I., Andre, I., Ferraz, J. C., and Cumano, A. (2000) Characterization of T cell precursor activity in the murine fetal thymus: evidence for an input of T cell precursors between days 12 and 14 of gestation. Eur. J. Immunol. 30, 2201–2210.PubMedGoogle Scholar
  66. 66.
    Bennett, A. R., Farley, A., Blair, N. R, Gordon, J., Sharp, L., and Blackburn, C. C. (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814.PubMedCrossRefGoogle Scholar
  67. 67.
    Klug, D. B., Carter, C., Gimenez-Conti, I. B., and Richie, E. R. (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842–2845.PubMedGoogle Scholar
  68. 68.
    Jenkinson, W. E., Rossi, S. W., Jenkinson, E. J., and Anderson, G. (2005) Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech. Dev. 122, 1294–1299.PubMedCrossRefGoogle Scholar
  69. 69.
    Van Vliet, E., Melis, M., and Van Ewijk, W. (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur. J. Immunol. 14, 524–529.PubMedCrossRefGoogle Scholar
  70. 70.
    Cordier, A. C. and Heremans, J. R (1975) Nude mouse embryo: ectodermal nature of the primordial thymic defect. Scand. J. Immunol. 4, 193–196.PubMedCrossRefGoogle Scholar
  71. 71.
    Le Douarin, N. M. and Jotereau, R V. (1975) Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17–40.PubMedCrossRefGoogle Scholar
  72. 72.
    Gordon, J., Wilson, V. A., Blair, N. R. et al. (2004) Functional evidence for a single endodermal origin for the thymic epithelium. Nat. Immunol. 5, 546–553.PubMedCrossRefGoogle Scholar
  73. 73.
    Blackburn, C. C. and Manley, N. R. (2004) Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4, 278–289.PubMedCrossRefGoogle Scholar
  74. 74.
    Manley, N. R. and Blackburn, C. C. (2003) A developmental look at thymus organogenesis: where do the non-hematopoietic cells in the thymus come from? Curr. Opin. Immunol. 15, 225–232.PubMedCrossRefGoogle Scholar
  75. 75.
    Schluep, M., Willcox, N., Ritter, M. A., Newsom-Davis, J., Larche, M., and Brown, A. N. (1988) Myasthenia gravis thymus: clinical, histological and culture correlations. J. Autoimmun. 1, 445–467.PubMedCrossRefGoogle Scholar
  76. 76.
    Blackburn, C. C., Augustine, C. L., Li, R., et al. (1996) The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl. Acad. Sci. USA 93, 5742–5746.PubMedCrossRefGoogle Scholar
  77. 77.
    Godfrey, D. I., Izon, D. J., Tucek, C. L., Wilson, T. J., and Boyd, R. L. (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunol. Today 70, 66–74.Google Scholar
  78. 78.
    Hollander, G. A., Wang, B., Nichogiannopoulou, A., et al. (1995) Developmental control point in the induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373, 350–353.PubMedCrossRefGoogle Scholar
  79. 79.
    Gill, J., Malin, M., Hollander, G. A., and Boyd, R. (2002) Generation of a com-plete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat. Immunol. 3, 635–642.PubMedCrossRefGoogle Scholar
  80. 80.
    Rodewald, H. R., Paul, S., Haller, C., Bluethmann, H., and Blum, C. (2001) Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768.PubMedCrossRefGoogle Scholar
  81. 81.
    Klug, D. B., Crouch, E., Carter, C., Coghlan, L., Conti, C. J., and Richie, E. R. (2000) Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial andT cell development. J. Immunol. 164, 1881–1888.PubMedGoogle Scholar
  82. 82.
    Norris, E. H. (1938) The morphogenesis and histogenesis of the thymus gland in man: in which the origin of the Hassall’s corpuscle of the human thymus is discovered. Contr. Embryol. Carnegie Instn. 27, 191–207.Google Scholar
  83. 83.
    Weller, G. L. (1933) Development of the thyroid, parathyroid and thymus glands in man. Cont. Embryol. 141, 95–138.Google Scholar
  84. 84.
    Van Dyke, J. H. (1941) On the origin of accessory thymus tissue, thymus IV: the occurrence in man. Anat. Rec. 79, 179–209.CrossRefGoogle Scholar
  85. 85.
    Lampert, I. A. and Ritter, M. A. (1988) The origin of the diverse epithelial cells of the thymus: is there a common stem cell? In: Thymus Update, (Kendall, M. D. and Ritter, M. A., eds.), Harwood Academic, UK, pp. 5–25.Google Scholar
  86. 86.
    Lobach, D. F. and Haynes, B. F. (1986) Ontogeny of the human thumus during fetal development. J. Clin. Immunol. 7, 81–97.CrossRefGoogle Scholar
  87. 87.
    Auerbach, R. (1960) Morphogenetic interactions in the development of the mouse thymus gland. Dev. Biol. 2, 271–284.PubMedCrossRefGoogle Scholar
  88. 88.
    Bockman, D. E. and Kirby, M. L. (1984) Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500.PubMedCrossRefGoogle Scholar
  89. 89.
    Revest, J. M., Suniara, R. K., Kerr, K., Owen, J. J., and Dickson, C. (2001) Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167, 1954–1961.PubMedGoogle Scholar
  90. 90.
    Shinohara, T. and Honjo, T. (1997) Studies in vitro on the mechanism of the epithelial/mesenchymal interaction in the early fetal thymus. Eur. J. Immunol. 27, 522–529.PubMedCrossRefGoogle Scholar
  91. 91.
    Anderson, G. and Jenkinson, E. J. (2001) Lymphostromal interactions in thymic development and function. Nat. Rev. Immunol. 1, 31–40.PubMedCrossRefGoogle Scholar
  92. 92.
    Ritter, M. A. and Boyd, R. L. (1993) Development in the thymus: it takes two to tango. Immunol. Today 14, 462–469.PubMedCrossRefGoogle Scholar
  93. 93.
    Farr, A., Nelson, A., Hosier, S., and Kim, A. (1993) A novel cytokine-responsive cell surface glycoprotein defines a subset of medullary thymic epithelium in situ. J. Immunol. 150, 1160–1171.PubMedGoogle Scholar
  94. 94.
    Ropke, C. and Elbroend, J. (1992) Human thymic epithelial cells in serum-free culture: nature and effects on thymocyte cell lines. Dev. Immunol. 2, 111–121.PubMedCrossRefGoogle Scholar
  95. 95.
    Galy, A. H. and Spits, H. (1992) CD40 is functionally expressed on human thymic epithelial cells. J. Immunol. 149, 775–782.PubMedGoogle Scholar
  96. 96.
    Colic, M., Pejnovic, N., Kataranovski, M., Popovic, L., Gassic, S., and Dujic, A. (1992) Interferon gamma alters the phenotype of rat thymic epithelial cells in culture and increases interleukin-6 production. Dev. Immunol. 2, 151–160.PubMedCrossRefGoogle Scholar
  97. 97.
    Montgomery, R. A. and Dallman, M. J. (1991) Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction. J. Immunol. 147, 554–560.PubMedGoogle Scholar
  98. 98.
    Le, P. T., Lazorick, S., Whichard, L. P., Haynes, B. E, and Singer, K. H. (1991) Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a posttranscriptional level. J. Exp. Med. 174, 1147–1157.PubMedCrossRefGoogle Scholar
  99. 99.
    Galy, A. H. and Spits, H. (1991) IL-1, IL-4, and IFN-gamma differentially regulate cytokine production and cell surface molecule expression in cultured human thymic epithelial cells. J. Immunol. 147, 3823–3830.PubMedGoogle Scholar
  100. 100.
    Dalloul, A. H., Arock, M., Fourcade, C., et al. (1991) Human thymic epithelial cells produce interleukin-3. Blood 77, 69–74.PubMedGoogle Scholar
  101. 101.
    Colic, M., Pejnovic, N., Kataranovski, M., Stojanovic, N., Terzic, T., and Dujic, A. (1991) Rat thymic epithelial cells in culture constitutively secrete IL-1 and IL-6. Int. Immunol. 3, 1165–1174.PubMedCrossRefGoogle Scholar
  102. 102.
    Cohen-Kaminsky, S., Delattre, R. M., Devergne, O., et al. (1991) Synergistic induction of interleukin-6 production and gene expression in human thymic epithelial cells by LPS and cytokines. Cell. Immunol. 138, 79–93.PubMedCrossRefGoogle Scholar
  103. 103.
    Barcena, A., Sanchez, M. J., de la Pompa, J. L., Toribio, M. L., Kroemer, G., and Martinez, A. C. (1991) Involvement of the interleukin 4 pathway in the generation of functional gamma delta T cells from human pro-T cells. Proc. Natl. Acad. Sci. USA 88, 7689–7693.PubMedCrossRefGoogle Scholar
  104. 104.
    Le, P. T., Lazorick, S., Whichard, L. P., et al. (1990) Human thymic epithelial cells produce IL-6, granulocyte-monocyte-CSF, and leukemia inhibitory factor. J. Immunol. 145, 3310–3315.PubMedGoogle Scholar
  105. 105.
    Erickson, M., Morkowski, S., Lehar, S., et al. (2002) Regulation of thymic epithelium by keratinocyte growth factor. Blood 100, 3269–3278.PubMedCrossRefGoogle Scholar
  106. 106.
    Jenkinson, W. E., Jenkinson, E. J., and Anderson, G. (2003) Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J. Exp. Med. 198, 325–332.PubMedCrossRefGoogle Scholar
  107. 107.
    Hu, T., Yamagishi, H., Maeda, J., McAnally, J., Yamagishi, C., and Srivastava, D. (2004) Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Development 131, 5491–5502.PubMedCrossRefGoogle Scholar
  108. 108.
    Xu, H., Morishima, M., Wylie, J. N., et al. (2004) Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 131, 3217–3227.PubMedCrossRefGoogle Scholar
  109. 109.
    Chapman, D. L., Garvey, N., Hancock, S., et al. (1996) Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev. Dyn. 206, 379–390.PubMedCrossRefGoogle Scholar
  110. 110.
    Lindsay, E. A., Botta, A., Jurecic, V., et al. (1999) Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383.PubMedGoogle Scholar
  111. 111.
    Scambler, P. J. (2000) The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426.PubMedCrossRefGoogle Scholar
  112. 112.
    Taddei, I., Morishima, M., Huynh, T., and Lindsay, E. A. (2001) Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q1 1 syndromes. Proc. Natl. Acad. Sci. USA 98, 11,428–11,431.PubMedCrossRefGoogle Scholar
  113. 113.
    Paylor, R., McIlwain, K. L., McAninch, R., et al. (2001) Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum. Mol. Genet. 10, 2645–2650.PubMedCrossRefGoogle Scholar
  114. 114.
    Jerome, L. A. and Papaioannou, V. E. (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet. 27, 286–291.PubMedCrossRefGoogle Scholar
  115. 115.
    Lindsay, E. A., Vitelli, F., Su, H., et al. (2001) Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101.PubMedCrossRefGoogle Scholar
  116. 116.
    Merscher, S., Funke, B., Epstein, J. A., et al. (2001) TBX1 is responsible for car diovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629.PubMedCrossRefGoogle Scholar
  117. 117.
    Xu, H., Cerrato F, and Baldini, A. (2005) Timed mutation and cell-fate mapping reveal reiterated roles of Tbx1 during embryogenesis, and a crucial function during segmentation of the pharyngeal system via regulation of endoderm expansion. Development 132, 4387–4395.PubMedCrossRefGoogle Scholar
  118. 118.
    Krumlauf, R. (1994) Hox genes in vertebrate development. Cell 78, 191–201.PubMedCrossRefGoogle Scholar
  119. 119.
    Manley, N. R. and Capecchi, M. R. (1998) Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev. Biol. 195, 1–15.PubMedCrossRefGoogle Scholar
  120. 120.
    Manley, N. R. and Capecchi, M. R. (1995) The role of Hoxa-3 in mouse thymus and thyroid development. Development 121, 1989–2003.PubMedGoogle Scholar
  121. 121.
    Neubuser, A., Koseki, H., and Balling, R. (1995) Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev. Biol. 170, 701–716.PubMedCrossRefGoogle Scholar
  122. 122.
    Wallin, J., Eibel, H., Neubuser, A., Wilting, J., Koseki, H., and Balling, R. (1996) Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23–30.PubMedGoogle Scholar
  123. 123.
    Su, D. M. and Manley, N. R. (2000) Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development. J. Immunol. 164, 5753–5760.PubMedGoogle Scholar
  124. 124.
    Su, D., Ellis, S., Napier, A., Lee, K., and Manley, N. R. (2001) Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev. Biol. 236, 316–329.PubMedCrossRefGoogle Scholar
  125. 125.
    Hetzer-Egger, C., Schorpp, M., Haas-Assenbaum, A., Balling, R., Peters, H., and Boehm, T. (2002) Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175–1181.PubMedCrossRefGoogle Scholar
  126. 126.
    Bonini, N. M., Leiserson, W. M., and Benzer, S. (1993) The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell 72, 379–395.PubMedCrossRefGoogle Scholar
  127. 127.
    Xu, P. X., Zheng, W., Laclef, C., et al. (2002) Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development 129, 3033–3044.PubMedGoogle Scholar
  128. 128.
    Xu, P. X., Woo, I., Her, H., Beier, D. R., and Maas, R. L. (1997) Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode. Development 124, 219–231.PubMedGoogle Scholar
  129. 129.
    Oliver, G., Mailhos, A., Wehr, R., Copeland, N. G., Jenkins, N. A., and Gruss, P. (1995) Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055.PubMedGoogle Scholar
  130. 130.
    Li, X., Oghi, K. A., Zhang, J., et al. (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426, 247–254.PubMedCrossRefGoogle Scholar
  131. 131.
    Pignoni, F., Hu, B., Zavitz, K. H., Xiao, J., Garrity, P. A., and Zipursky, S. L. (1997) The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91, 881–891.PubMedCrossRefGoogle Scholar
  132. 132.
    Conway, S. J., Bundy, J., Chen, J., Dickman, E., Rogers, R., and Will, B. M. (2000) Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc. Res. 47, 314–328.PubMedCrossRefGoogle Scholar
  133. 133.
    Epstein, J. A., Li, J., Lang, D., et al. (2000) Migration of cardiac neural crest cells in Splotch embryos. Development 127, 1869–1878.PubMedGoogle Scholar
  134. 134.
    Machado, A. E, Martin, L. J., and Collins, M. D. (2001) Pax3 and the splotch mutations: structure, function, and relationship to teratogenesis, including gene-chemical interactions. Curr. Pharm. Des. 7, 751–785.PubMedCrossRefGoogle Scholar
  135. 135.
    Boehm, T., Bleul, C. C., and Schorpp, M. (2003) Genetic dissection of thymus development in mouse and zebrafish. Immunol. Rev. 195, 15–27.PubMedCrossRefGoogle Scholar
  136. 136.
    Cordier, A. C. (1974) Ultrastructure of the thymus in “Nude” mice. J. Ultrastruct. Res. 47, 26–40.PubMedCrossRefGoogle Scholar
  137. 137.
    Gordon, J., Bennett, A. R., Blackburn, C. C., and Manley, N. R. (2001) Gcm2 and Foxn1 mark early parathyroid-and thymus-specific domains in the developing third pharyngeal pouch. Mech. Dev. 103, 141–143.PubMedCrossRefGoogle Scholar
  138. 138.
    Itoi, M., Kawamoto, H., Katsura, Y., and Amagai, T. (2001) Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage. Int. Immunol. 13, 1203–1211.PubMedCrossRefGoogle Scholar
  139. 139.
    Balciunaite, G., Keller, M. P., Balciunaite, E., et al. (2002) Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat. Immunol. 3, 1102–1108.PubMedCrossRefGoogle Scholar
  140. 140.
    Nehls, M., Kyewski, B., Messerle, M., et al. (1996) Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886–889.PubMedCrossRefGoogle Scholar
  141. 141.
    Flanagan, S. P. (1966) ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8, 295–309.PubMedCrossRefGoogle Scholar
  142. 142.
    Gunther, T., Chen, Z. E, Kim, J., et al. (2000) Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406, 199–203.PubMedCrossRefGoogle Scholar
  143. 143.
    Brissette, J. L., Li, J., Kamimura, J., Lee, D., and Dotto, G. P. (1996) The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev. 10, 2212–2221.PubMedCrossRefGoogle Scholar
  144. 144.
    Janes, S. M., Ofstad, T. A., Campbell, D. H., Watt, F. M., and Prowse, D. M. (2004) Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 andAkt. J. Cell Sci. 117, 4157–4168.PubMedCrossRefGoogle Scholar
  145. 145.
    Bleul, C. C. and Boehm, T. (2001) Laser capture microdissection-based expression profiling identifies PD1-ligand as a target of the nude locus gene product. Eur. J. Immunol. 31, 2497–2503.PubMedCrossRefGoogle Scholar
  146. 146.
    Su, D. M., Navarre, S., Oh, W. J., Condie, B. G., and Manley, N. R. (2003) A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat. Immunol. 4, 1128–1135.PubMedCrossRefGoogle Scholar
  147. 147.
    Nishimura, H., Agata, Y., Kawasaki, A., et al. (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int. Immunol. 8, 773–780.PubMedCrossRefGoogle Scholar
  148. 148.
    Nishimura, H., Honjo, T., and Minato, N. (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J. Exp. Med. 191, 891–898.PubMedCrossRefGoogle Scholar
  149. 149.
    Patel, S. R., Gordon, J., Mahbub, F., Blackburn, C. C., and Manley, N. (2006) Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expr Patterns 6(8), 794–799.PubMedCrossRefGoogle Scholar
  150. 150.
    Tsai, P. T., Lee, R. A., and Wu, H. (2003) BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102, 3947–3953.PubMedCrossRefGoogle Scholar
  151. 151.
    Bleul, C. C. and Boehm, T. (2005) BMP signaling is required for normal thymus development. J. Immunol. 175, 5213–5221.PubMedGoogle Scholar
  152. 152.
    Abu-Issa, R., Smyth, G., Smoak, I., Yamamura, K., and Meyers, E. N. (2002) Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129, 4613–4625.PubMedGoogle Scholar
  153. 153.
    Frank, D. U., Fotheringham, L. K., Brewer, J. A., et al. (2002) An Fgf8 mouse mutant phenocopies human 22q1 1 deletion syndrome. Development 129, 4591–4603.PubMedGoogle Scholar
  154. 154.
    Conway, S. J., Henderson, D. J., and Copp, A. J. (1997) Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514.PubMedGoogle Scholar
  155. 155.
    Mitchell, P. J., Timmons, P. M., Hebert, J. M., Rigby, P. W., and Tjian, R. (1991) Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev. 5, 105–119.PubMedCrossRefGoogle Scholar
  156. 156.
    Dencker, L., Annerwall, E., Busch, C., and Eriksson, U. (1990) Localization of specific retinoid-binding sites and expression of cellular retinoic-acid-binding protein (CRABP) in the early mouse embryo. Development 110, 343–352.PubMedGoogle Scholar
  157. 157.
    Macatee, T. L., Hammond, B. P., Arenkiel, B. R., Francis, L., Frank, D. U., and Moon, A. M. (2003) Ablation of specific expression domains reveals discrete functions of ectoderm-and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development 130, 6361–6374.PubMedCrossRefGoogle Scholar
  158. 158.
    Suniara, R. K., Jenkinson, E. J., and Owen, J. J. (2000) An essential role for thymic mesenchyme in early T cell development. J. Exp. Med. 191, 1051–1056.PubMedCrossRefGoogle Scholar
  159. 159.
    Campbell, J. J., Pan, J., and Butcher, E. C. (1999) Cutting edge: developmental switches in chemokine responses during T cell maturation. J. Immunol. 163, 2353–2357.PubMedGoogle Scholar
  160. 160.
    Wendling, O., Dennefeld, C., Chambon, P., and Mark, M. (2000) Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development 127, 1553–1562.PubMedGoogle Scholar
  161. 161.
    Ghyselinck, N. B., Dupe, V., Dierich, A., et al. (1997) Role of the retinoic acid receptor beta (RARbeta) during mouse development. Int. J. Dev. Biol. 41, 425–447.PubMedGoogle Scholar
  162. 162.
    Kanariou, M., Huby, R., Ladyman, H., et al. (1989) Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin. Exp. Immunol. 78, 263–270.PubMedGoogle Scholar
  163. 163.
    Imami, N., Ladyman, H. M., Spanopoulou, E., and Ritter, M. A. (1992) A novel adhesion molecule in the murine thymic microenvironment: functional and biochemical analysis. Dev. Immunol. 2, 161–173.PubMedCrossRefGoogle Scholar
  164. 164.
    Rouse, R. V., Bolin, L. M., Bender, J. R., and Kyewski, B. A. (1988) Monoclonal antibodies reactive with subsets of mouse and human thymic epithelial cells. J. Histochem. Cytochem. 36, 1511–1517.PubMedCrossRefGoogle Scholar
  165. 165.
    Vicari, A., Abehsira-Amar, O., Papiernik, M., Boyd, R. L., and Tucek, C. L. (1994) MTS-32 monoclonal antibody defines CD4+8-thymocyte subsets that differ in their maturation level, lymphokine secretion, and selection patterns. J. Immunol. 152, 2207–2213.PubMedGoogle Scholar
  166. 166.
    MacNeil, I., Kennedy, J., Godfrey, D. L, et al. (1993) Isolation of a cDNA encoding thymic shared antigen-1. A new member of the Ly6 family with a possible role in T cell development. J. Immunol. 151, 6913–6923.PubMedGoogle Scholar
  167. 167.
    Randle, E. S., Waanders, G. A., Masciantonio, M., Godfrey, D.I., and Boyd, R. L. (1993) A lymphostromal molecule, thymic shared Ag-1, regulates early thymocyte development in fetal thymus organ culture. J. Immunol. 151, 6027–6035.PubMedGoogle Scholar
  168. 168.
    Ivanov, V. and Ceredig, R. (1992) Transcription factors in mouse fetal thymus development. Int. Immunol. 4, 729–737.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2007

Authors and Affiliations

  • Craig S. Nowell
    • 1
  • Alison M. Farley
    • 1
  • C. Clare Blackburn
    • 1
  1. 1.Institute for Stem Cell ResearchUniversity of EdinburghEdinburghUK

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