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Sonic hedgehog signalling in T-cell development and activation

Nature Reviews Immunology volume 7, pages 726–735 (2007)Cite this article

Key Points

  • Components of the hedgehog signalling pathway are expressed in human and mouse thymi by both stromal and lymphoid cells.

  • Analysis of sonic hedgehog homologue (Shh)−/−, glioma-associated oncogene 3 (Gli3)−/− and conditional smoothened (Smo)−/− thymi revealed that SHH signalling is necessary for proliferation and survival of double-negative (DN) T cells and for efficient differentiation from DN1 to DN2.

  • The function of hedgehog signalling at the transition from DN to double-positive (DP) cells is controversial, with experimental evidence supporting three possible interpretations: that hedgehog is a negative regulator of differentiation to the DP stage that counteracts the pre-TCR (T-cell receptor) signal; that SHH is a positive regulator of this transition; or, that hedgehog signalling has no influence on thymocyte differentiation after the DN2 stage. The evidence for these three hypotheses is discussed.

  • Analysis of Shh−/− and Gli2ΔN2 transgenics revealed that SHH signalling influences TCR repertoire selection, CD4–CD8-lineage commitment and differentiation from DP to single-positive (SP) cells, most probably by reducing TCR signal strength.

  • The involvement of SHH signalling in peripheral T-cell function is controversial with different experimental systems supporting three possible interpretations: that hedgehog is a negative regulator of peripheral T-cell activation; that hedgehog is necessary for efficient T-cell activation; or that hedgehog signalling is not involved in T-cell activation. Evidence in favour of these three different models is discussed.

Abstract

The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH-induced signalling is not only important for the differentiation and proliferation of early thymocyte progenitors, but also for modulating T-cell receptor signalling during repertoire selection, with implications for positive selection, CD4 versus CD8 lineage commitment, and clonal deletion of autoreactive cells. We also review the influence of hedgehog signalling in peripheral T-cell activation.

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Figure 1: SHH signalling.
Figure 2: SHH signalling during thymocyte development
Figure 3: SHH signalling influences TCR repertoire selection.

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References

  1. Radtke, F., Wilson, A., Mancini, S. J. & MacDonald, H. R. Notch regulation of lymphocyte development and function. Nature Immunol. 5, 247–253 (2004).

    Article  CAS  Google Scholar 

  2. 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 

  3. Guidos, C. J. Synergy between the pre-T cell receptor and Notch: cementing the αβ lineage choice. J. Exp. Med. 203, 2233–2237 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Verbeek, S. et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Schilham, M. W. et al. Critical involvement of Tcf-1 in expansion of thymocytes. J. Immunol. 161, 3984–3991 (1998).

    CAS  PubMed  Google Scholar 

  6. Mulroy, T., McMahon, J. A., Burakoff, S. J., McMahon, A. P. & Sen, J. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur. J. Immunol. 32, 967–971 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Hager-Theodorides, A. L. et al. Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J. Immunol. 169, 5496–5504 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Cejalvo, T. et al. Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development. Immunology 121, 94–104 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsai, P. T., Lee, R. A. & Wu, H. BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102, 3947–3953 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Graf, D., Nethisinghe, S., Palmer, D. B., Fisher, A. G. & Merkenschlager, M. The developmentally regulated expression of Twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development. J. Exp. Med. 196, 163–171 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Varas, A. et al. The role of morphogens in T-cell development. Trends Immunol. 24, 197–206 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Ingham, P. W. & Placzek, M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nature Rev. Genet. 7, 841–850 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Jia, J. & Jiang, J. Decoding the Hedgehog signal in animal development. Cell. Mol. Life. Sci. 63, 1249–1265 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001).

    Article  CAS  Google Scholar 

  16. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Outram, S. V., Varas, A., Pepicelli, C. V. & Crompton, T. Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte. Immunity 13, 187–197 (2000). First description of hedgehog signalling in thymocyte development: treatment of mouse FTOC with SHH protein arrests thymocyte development at the DN3 stage after TCRb chain rearrangement, whereas neutralization of endogenous hedgehog signalling by hedgehog-specific antibody treatment increased DP cell production.

    Article  CAS  PubMed  Google Scholar 

  18. Briscoe, J. & Ericson, J. The specification of neuronal identity by graded Sonic Hedgehog signalling. Semin. Cell Dev. Biol. 10, 353–362 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Hooper, J. E. & Scott, M. P. Communicating with Hedgehogs. Nature Rev. Mol. Cell Biol. 6, 306–317 (2005).

    Article  CAS  Google Scholar 

  21. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Koebernick, K. & Pieler, T. Gli-type zinc finger proteins as bipotential transducers of Hedgehog signaling. Differentiation 70, 69–76 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Matise, M. P. & Joyner, A. L. Gli genes in development and cancer. Oncogene 18, 7852–7859 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Park, H. L. et al. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127, 1593–1605 (2000).

    CAS  PubMed  Google Scholar 

  25. Aza-Blanc, P., Lin, H. Y., Ruiz i Altaba, A. & Kornberg, T. B. Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities. Development 127, 4293–4301 (2000).

    PubMed  Google Scholar 

  26. Sasaki, H., Nishizaki, Y., Hui, C., Nakafuku, M. & Kondoh, H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126, 3915–3924 (1999).

    CAS  PubMed  Google Scholar 

  27. Barnfield, P. C., Zhang, X., Thanabalasingham, V., Yoshida, M. & Hui, C. C. Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 73, 397–405 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Mo, R. et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124, 113–123 (1997).

    CAS  PubMed  Google Scholar 

  29. Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. & Joyner, A. L. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129, 4753–4761 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Stamataki, D., Ulloa, F., Tsoni, S. V., Mynett, A. & Briscoe, J. A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev. 19, 626–641 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tenzen, T. et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 10, 647–656 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Allen, B. L., Tenzen, T. & McMahon, A. P. The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev. 21, 1244–1257 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mebius, R. E. et al. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3− cells, as well as macrophages. J. Immunol. 166, 6593–6601 2001).

    Article  CAS  PubMed  Google Scholar 

  35. Kawamoto, H., Ikawa, T., Ohmura, K., Fujimoto, S. & Katsura, Y. T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver. Immunity 12, 441–450 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Godfrey, D. I. & Zlotnik, A. Control points in early T-cell development. Immunol. Today 14, 547–553 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Ceredig, R. & Rolink, T. A positive look at double-negative thymocytes. Nature Rev. Immunol. 2, 888–897 (2002).

    Article  CAS  Google Scholar 

  38. Borowski, C. et al. On the brink of becoming a T cell. Curr. Opin. Immunol. 14, 200–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Michie, A. M. & Zuniga-Pflucker, J. C. Regulation of thymocyte differentiation: pre-TCR signals and β-selection. Semin. Immunol. 14, 311–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Misslitz, A., Bernhardt, G. & Forster, R. Trafficking on serpentines: molecular insight on how maturating T cells find their winding paths in the thymus. Immunol. Rev. 209, 115–128 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Misslitz, A. et al. Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Petrie, H. T. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol. Rev. 189, 8–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Petrie, H. T., Tourigny, M., Burtrum, D. B. & Livak, F. Precursor thymocyte proliferation and differentiation are controlled by signals unrelated to the pre-TCR. J. Immunol. 165, 3094–3098 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. von Boehmer, H. Shaping the T cell repertoire. J. Immunol. 176, 3–4 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. von Boehmer, H. & Kisielow, P. Negative selection of the T-cell repertoire: where and when does it occur? Immunol. Rev. 209, 284–289 (2006).

    Article  PubMed  Google Scholar 

  46. Germain, R. N. T-cell development and the CD4–CD8 lineage decision. Nature Rev. Immunol. 2, 309–322 (2002).

    Article  CAS  Google Scholar 

  47. Kappes, D. J., He, X. & He, X. CD4—CD8 lineage commitment: an inside view. Nature Immunol. 6, 761–766 (2005).

    Article  CAS  Google Scholar 

  48. Bommhardt, U., Basson, M. A., Krummrei, U. & Zamoyska, R. Activation of the extracellular signal-related kinase/mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus. J. Immunol. 163, 715–722 (1999).

    CAS  PubMed  Google Scholar 

  49. Ladi, E., Yin, X., Chtanova, T. & Robey, E. A. Thymic microenvironments for T cell differentiation and selection. Nature Immunol. 7, 338–343 (2006).

    Article  CAS  Google Scholar 

  50. Petrie, H. T. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nature Rev. Immunol. 3, 859–366 (2003).

    Article  CAS  Google Scholar 

  51. Petrie, H. T. & Zuniga-Pflucker, J. C. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649–679 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Manley, N. R. Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin. Immunol. 12, 421–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Suniara, R. K., Jenkinson, E. J. & Owen, J. J. Studies on the phenotype of migrant thymic stem cells. Eur. J. Immunol. 29, 75–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Lind, E. F., Prockop, S. E., Porritt, H. E. & Petrie, H. T. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194, 127–134 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Benz, C., Heinzel, K. & Bleul, C. C. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Liu, C. et al. Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108, 2531–2539 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Hager-Theodorides, A. L., Rowbotham, N. J., Outram, S. V., Dessens, J. T. & Crompton, T. β-selection: abundance of TCRβ-/γδ- CD44- CD25- (DN4) cells in the foetal thymus. Eur. J. Immunol. 37, 487–500 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jotereau, F., Heuze, F., Salomon-Vie, V. & Gascan, H. Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J. Immunol. 138, 1026–1030 (1987).

    CAS  PubMed  Google Scholar 

  59. David-Fung, E. S. et al. Progression of regulatory gene expression states in fetal and adult pro-T-cell development. Immunol. Rev. 209, 212–236 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shah, D. K. et al. Reduced thymocyte development in sonic hedgehog knockout embryos. J. Immunol. 172, 2296–2306 (2004). Analysis of Shh−/− thymus reveals that SHH is necessary for efficient proliferation of DN thymocytes, and for differentiation from the DN1 to DN2, and from DN to the DP stage.

    Article  CAS  PubMed  Google Scholar 

  61. Rowbotham, N. J. et al. Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation. Blood 109, 3757–3766 (2007). SHH and activation of the SHH-signalling pathway in developing thymocytes and T-cells influence TCR repertoire selection and differentiation from DP to SP cell, and inhibit T-cell activation and proliferation, most probably by modulating the strength of the TCR signal.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hager-Theodorides, A. L., Dessens, J. T., Outram, S. V. & Crompton, T. The transcription factor Gli3 regulates differentiation of fetal CD4− CD8− double-negative thymocytes. Blood 106, 1296–1304 (2005). Analysis of Gli3−/− thymus reveals that GLl3 is necessary for differentiation from the DN1 to DN2, and from DN3 to the DP stage during fetal thymocyte development.

    Article  CAS  PubMed  Google Scholar 

  63. Virts, E. L., Phillips, J. A. & Thoman, M. L. A novel approach to thymic rejuvenation in the aged. Rejuvenation Res. 9, 134–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Andaloussi, A. E. et al. Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus. Nature Immunol. 7, 418–426 (2006). Analysis of T-cell-lineage specific conditional SMO knockout mice confirms that hedgehog signalling is important for proliferation and survival of DN thymocytes and for differentiation from DN1 to DN2, but fails to reveal a role for the signalling pathway at later stages of T-cell development or in peripheral T-cell activation.

    Article  CAS  Google Scholar 

  65. Sacedon, R. et al. Expression of hedgehog proteins in the human thymus. J. Histochem. Cytochem. 51, 1557–1566 (2003). Expression of components of the hedgehog pathway in human stromal and lymphoid components of the thymus, revealing some species differences between human and mouse expression patterns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li, C. L. et al. Estrogen deficiency results in enhanced expression of Smoothened of the Hedgehog signaling in the thymus and affects thymocyte development. Int. Immunopharmacol. 2, 823–833 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. te Welscher, P. et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science 298, 827–830 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. te Welscher, P., Fernandez-Teran, M., Ros, M. A. & Zeller, R. Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev. 16, 421–426 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cayuso, J., Ulloa, F., Cox, B., Briscoe, J. & Marti, E. The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity. Development 133, 517–528 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Gutierrez-Frias, C. et al. Sonic hedgehog regulates early human thymocyte differentiation by counteracting the IL-7-induced development of CD34+ precursor cells. J. Immunol. 173, 5046–5053 (2004). In vitro experiments show that in the human system, the hedgehog pathway functions to maintain the CD34+ precursor pool by signalling for survival, modulating expression of the pro-apoptotic factor bax and the survival factor BCL-2, and counteracting interleukin-7 (IL-7)-induced proliferation and development.

    Article  CAS  PubMed  Google Scholar 

  72. Rahnama, F. et al. Inhibition of GLI1 gene activation by Patched1. Biochem. J. 394, 19–26 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ashe, H. L. & Briscoe, J. The interpretation of morphogen gradients. Development 133, 385–394 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Falk, I., Nerz, G., Haidl, I., Krotkova, A. & Eichmann, K. Immature thymocytes that fail to express TCRβ and/or TCRγδ proteins die by apoptotic cell death in the CD44–CD25– (DN4) subset. Eur. J. Immunol. 31, 3308–3317 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Mombaerts, P. et al. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature 360, 225–231 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    Article  CAS  PubMed  Google Scholar 

  78. Azzam, H. S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Sacedon, R. et al. Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis. J. Immunol. 174, 1456–1461 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Chan, V. S. et al. Sonic hedgehog promotes CD4+ T lymphocyte proliferation and modulates the expression of a subset of CD28-targeted genes. Int. Immunol. 18, 1627–1636 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Lowrey, J. A. et al. Sonic hedgehog promotes cell cycle progression in activated peripheral CD4+ T lymphocytes. J. Immunol. 169, 1869–1875 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Stewart, G. A. et al. Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells. J. Immunol. 169, 5451–5457 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Weerkamp, F., van Dongen, J. J. & Staal, F. J. Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia. Leukemia 20, 1197–1205 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Maillard, I., Fang, T. & Pear, W. S. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu. Rev. Immunol. 23, 945–974 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Grove, E. A., Tole, S., Limon, J., Yip, L. & Ragsdale, C. W. The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development 125, 2315–2325 (1998).

    CAS  PubMed  Google Scholar 

  86. Ulloa, F., Itasaki, N. & Briscoe, J. Inhibitory Gli3 activity negatively regulates Wnt/β-catenin signaling. Curr. Biol. 17, 545–550 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Dai, P. et al. Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes Dev. 16, 2843–2848 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bastida, M. F. et al. Levels of Gli3 repressor correlate with Bmp4 expression and apoptosis during limb development. Dev. Dyn. 231, 148–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Kuschel, S., Ruther, U. & Theil, T. A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Dev. Biol. 260, 484–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Tasaki, A. et al. Immunohistochemical staining of hedgehog pathway-related proteins in human thymomas. Anticancer Res. 25, 3697–3701 (2005).

    CAS  PubMed  Google Scholar 

  91. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

    Article  CAS  PubMed  Google Scholar 

  92. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Baron, M. H. Embryonic origins of mammalian hematopoiesis. Exp. Hematol. 31, 1160–1169 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Trowbridge, J. J., Scott, M. P. & Bhatia, M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc. Natl Acad. Sci. USA 103, 14134–14139 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39, 937–950 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Palma, V. & Ruiz i Altaba, A. Hedgehog–GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 131, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131, 5009–5019 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Ruiz i Altaba, A., Sanchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361–372 (2002).

    Article  CAS  Google Scholar 

  101. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev. Cancer. 3, 903–911 (2003).

    Article  Google Scholar 

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Acknowledgements

We thank N. Rowbotham and E. Drakopoulou for helpful discussions. S.V.O. is funded by the BBSRC, and A.L.H.-T. is funded by the Wellcome Trust.

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  1. Immunobiology Unit, University College London Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Tessa Crompton, Susan V. Outram & Ariadne L. Hager-Theodorides

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  1. Tessa Crompton
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  2. Susan V. Outram
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Correspondence to Tessa Crompton.

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Glossary

Morphogen

A protein that controls pattern formation by emanating from a localized source and creating a concentration gradient that regulates cell fate (proliferation, survival or differentiation) depending on the cell's position in the gradient.

Patterning

The process that coordinates progenitor-cell expansion and differentiation and establishes a non-random spatial formation of a tissue, organ or organism.

Positive selection

A process that leads to the survival of immature thymocytes that express a T-cell receptor that binds with an appropriate affinity to self MHC.

Negative selection

A process that results in the elimination of thymocytes expressing a T-cell receptor that binds with high affinity to self.

Fetal thymus organ culture

(FTOC). A system for culturing fetal thymi on a filter suspended over culture medium, which allows the growth of the organ for a longer period of time than the viability of the embryo allows and/or under various experimental conditions, for example by the addition of growth factors in the medium.

Recombination-activating gene 1 (RAG 1) and RAG2 proteins

Proteins that are both necessary for the recombination of the lymphocyte (T and B cell) receptor (TCR and BCR) loci. The recombination of T- and B-cell receptor loci is in turn necessary for the expression of functional TCR or BCR on T- or B-cell surface respectively and development of mature lymphocytes.

β-selection

A process leading, through a cell autonomous signalling cascade, to the proliferation and survival of thymocytes that have successfully recombined the β-chain of the T-cell receptor locus to express a functional pre-TCR on their cell surface.

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Crompton, T., Outram, S. & Hager-Theodorides, A. Sonic hedgehog signalling in T-cell development and activation. Nat Rev Immunol 7, 726–735 (2007). https://doi.org/10.1038/nri2151

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