Skip to main content
SpringerLink
Log in

Epithelial Stem Cells and the Development of the Thymus, Parathyroid, and Skin

  • Chapter
Regulatory Networks in Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

  • 1369 Accesses

Abstract

It is evident that epithelial tissues are able to self-renew not only during normal homeostasis but also following damage. How this occurs has major implications for the development of therapies for degenerative conditions. While not fully understood, tissue self-renewal through the activation of endogenous stem cells is a likely possibility, however, regeneration through replication of pre-existing transit amplifying or mature cells may also occur. The current consensus is that stem cells reside in tissue-specific niches that are important in maintaining the stem cell state and exposing the cells to various differentiation signals. A comparative analysis of these niches from diverse tissue types has revealed similarities in signaling pathways for the maintenance, lineage determination, and differentiation of epithelial stem cells, but also has shown discrete differences. This review examines these issues, with a particular focus on the development of thymic epithelial cells. Understanding the nature of epithelial stem cell self-renewal and differentiation and the niches in which they reside will have important future clinical implications in regenerative medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Schock F, Perrimon N. Molecular mechanisms of epithelial morphogenesis. Annu Rev Cell Dev Biol. 2002;18:463–93.

    PubMed  CAS  Google Scholar 

  2. Slack JM. Stem cells in epithelial tissues. Science. 2000;287 (5457):1431–3.

    PubMed  CAS  Google Scholar 

  3. Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.

    PubMed  CAS  Google Scholar 

  4. Eakin GS, Behringer RR. Gastrulation in other mammals and humans. In: Stern CD, editor. Gastrulation: From cells to embryo. New York: Cold Spring Harbor Laboratory Press; 2004. pp. 275–87.

    Google Scholar 

  5. Tam PPL, Gad JM. Gastrulation in the mouse embryo. In: Stern CD, editor. Gastrulation: From cells to embryo. New York: Cold Spring Harbor Laboratory Press; 2004. pp. 233–62.

    Google Scholar 

  6. Tam PP, Loebel DA. Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet. 2007;8(5):368–81.

    PubMed  CAS  Google Scholar 

  7. Li L, Xie T. Stem cell niche: structure and function. Annu Rev Cell Dev Biol. 2005;21:605–31.

    PubMed  CAS  Google Scholar 

  8. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    PubMed  CAS  Google Scholar 

  9. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000;18(4):399–404.

    PubMed  CAS  Google Scholar 

  10. Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche. Nature. 2001;414(6859):98–104.

    PubMed  CAS  Google Scholar 

  11. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4(1–2): 7–25.

    PubMed  CAS  Google Scholar 

  12. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell. 2004;116(6):769–78.

    PubMed  CAS  Google Scholar 

  13. Rizvi AZ, Wong MH. Epithelial stem cells and their niche: there’s no place like home. Stem Cells. 2005;23(2):150–65.

    PubMed  Google Scholar 

  14. Ohlstein B, Kai T, Decotto E, Spradling A. The stem cell niche: theme and variations. Curr Opin Cell Biol. 2004;16(6):693–9.

    PubMed  CAS  Google Scholar 

  15. Mitsiadis TA, Barrandon O, Rochat A, Barrandon Y, De Bari C. Stem cell niches in mammals. Exp Cell Res. 2007;313(16): 3377–85.

    PubMed  CAS  Google Scholar 

  16. Moore KA, Lemischka IR. Stem cells and their niches. Science. 2006;311(5769):1880–5.

    PubMed  CAS  Google Scholar 

  17. Mackenzie IC. Stem cell properties and epithelial malignancies. Eur J Cancer. 2006;42(9):1204–12.

    PubMed  CAS  Google Scholar 

  18. Yamashita YM, Jones DL, Fuller MT. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science. 2003;301(5639):1547–50.

    PubMed  CAS  Google Scholar 

  19. Perez-Moreno M, Jamora C, Fuchs E. Sticky business: orchestrating cellular signals at adherens junctions. Cell. 2003;112(4): 535–48.

    PubMed  CAS  Google Scholar 

  20. Etienne-Manneville S, Hall A. Cell polarity: Par6, aPKC and cytoskeletal crosstalk. Curr Opin Cell Biol. 2003;15(1):67–72.

    PubMed  CAS  Google Scholar 

  21. Yamashita YM, Fuller MT, Jones DL. Signaling in stem cell niches: lessons from the Drosophila germline. J Cell Sci. 2005;118(Pt 4):665–72.

    PubMed  CAS  Google Scholar 

  22. Betschinger J, Knoblich JA. Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr Biol. 2004;14(16):R674–85.

    PubMed  CAS  Google Scholar 

  23. Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. Bioessays. 2002;24(1):91–8.

    PubMed  Google Scholar 

  24. Lamprecht J. Symmetric and asymmetric cell division in rat corneal epithelium. Cell Tissue Kinet. 1990;23(3):203–16.

    PubMed  CAS  Google Scholar 

  25. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59–72.

    PubMed  CAS  Google Scholar 

  26. Claudinot S, Nicolas M, Oshima H, Rochat A, Barrandon Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc Natl Acad Sci U S A. 2005;102(41):14677–82.

    PubMed  CAS  Google Scholar 

  27. Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature. 2005;437(7056):275–80.

    PubMed  CAS  Google Scholar 

  28. Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science. 2000;287(5457):1427–30.

    PubMed  CAS  Google Scholar 

  29. Potten CS, Wilson JW, Robert L, Robert L, Joseph V. Adult epithelial tissue stem cells. In: Principles of tissue engineering. 3rd ed. Burlington: Academic Press; 2007. pp. 431–44.

    Google Scholar 

  30. Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol. 2004;16(6): 700–7.

    PubMed  CAS  Google Scholar 

  31. Blanpain C, Horsley V, Fuchs E. Epithelial stem cells: turning over new leaves. Cell. 2007;128(3):445–58.

    PubMed  CAS  Google Scholar 

  32. Hanna C, Bicknell DS, O’Brien JE. Cell turnover in the adult human eye. Arch. Ophthalmol. 1961;65:695–8.

    PubMed  CAS  Google Scholar 

  33. Potten CS, Saffhill R, Maibach HI. Measurement of the transit time for cells through the epidermis and stratum corneum of the mouse and guinea-pig. Cell Tissue Kinet. 1987;20(5):461–72.

    PubMed  CAS  Google Scholar 

  34. Chidgey A, Boyd RL, Hugo P. The thymic niche and thymopoiesis. In: Encyclopedia of life sciences. Chichester: John Wiley & Sons, Ltd; 2007.

    Google Scholar 

  35. Gillard GO, Farr AG. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J Immunol. 2006;176(10):5815–24.

    PubMed  CAS  Google Scholar 

  36. Gray DH, Seach N, Ueno T, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood. 2006;108(12):3777–85.

    PubMed  CAS  Google Scholar 

  37. Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118(5):635–48.

    PubMed  CAS  Google Scholar 

  38. Hennighausen L, Robinson GW. Information networks in the mammary gland. NatRev. 2005;6(9):715–25.

    CAS  Google Scholar 

  39. Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science. 2004;304(5675):1331–4.

    PubMed  CAS  Google Scholar 

  40. Kai T, Spradling A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature. 2004;428(6982):564–9.

    PubMed  CAS  Google Scholar 

  41. Potten CS, Grant HK. The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer. 1998;78(8):993–1003.

    PubMed  CAS  Google Scholar 

  42. Potten CS. Apoptosis in oral mucosa: lessons from the crypt. A commentary. Oral Dis. 2001;7(2):81–5.

    CAS  Google Scholar 

  43. Barrandon Y, Morgan JR, Mulligan RC, Green H. Restoration of growth potential in paraclones of human keratinocytes by a viral oncogene. Proc Natl Acad Sci U S A. 1989;86(11):4102–6.

    PubMed  CAS  Google Scholar 

  44. Ferraris C, Chaloin-Dufau C, Dhouailly D. Transdifferentiation of embryonic and postnatal rabbit corneal epithelial cells. Differentiation. 1994;57(2):89–96.

    PubMed  CAS  Google Scholar 

  45. Baba Y, Garrett KP, Kincade PW. Constitutively active beta-catenin confers multilineage differentiation potential on lymphoid and myeloid progenitors. Immunity. 2005;23(6):599–609.

    PubMed  CAS  Google Scholar 

  46. Nakagawa T, Nabeshima Y, Yoshida S. Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell. 2007;12(2):195–206.

    PubMed  CAS  Google Scholar 

  47. Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451(7175):141–6 .

    PubMed  CAS  Google Scholar 

  48. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    PubMed  CAS  Google Scholar 

  49. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    PubMed  CAS  Google Scholar 

  50. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    PubMed  CAS  Google Scholar 

  51. Byrne JA, Pedersen DA, Clepper LL, et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature. 2007;450(7169):497–502.

    PubMed  CAS  Google Scholar 

  52. Birchmeier C, Birchmeier W. Molecular aspects of mesenchymal-epithelial interactions. Annu Rev Cell Biol. 1993;9:511–40.

    PubMed  CAS  Google Scholar 

  53. Jenkinson WE, Jenkinson EJ, Anderson G. Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med. 2003;198(2):325–32.

    PubMed  CAS  Google Scholar 

  54. Capdevila J, Izpisua Belmonte JC. Patterning mechanisms controlling vertebrate limb development. Annu Rev Cell Dev Biol. 2001;17:87–132.

    PubMed  CAS  Google Scholar 

  55. Rendl M, Lewis L, Fuchs E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 2005;3(11):e331.

    PubMed  Google Scholar 

  56. Brittan M, Wright NA. Gastrointestinal stem cells. J Pathol. 2002;197(4):492–509.

    PubMed  Google Scholar 

  57. Marsh MN, Trier JS. Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum. II. Radioautographic studies. Gastroenterology. 1974;67(4):636–45.

    PubMed  CAS  Google Scholar 

  58. Cunha GR, Young P, Christov K, et al. Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme. Acta Anat (Basel). 1995;152(3):195–204.

    CAS  Google Scholar 

  59. Ferraris C, Chevalier G, Favier B, Jahoda CA, Dhouailly D. Adult corneal epithelium basal cells possess the capacity to activate epidermal, pilosebaceous and sweat gland genetic programs in response to embryonic dermal stimuli. Development. 2000;127(24):5487–95.

    PubMed  CAS  Google Scholar 

  60. Taylor RA, Cowin PA, Cunha GR, et al. Formation of human prostate tissue from embryonic stem cells. Nat Methods. 2006;3(3):179–81.

    PubMed  CAS  Google Scholar 

  61. Tsai RY. A molecular view of stem cell and cancer cell self-renewal. Int J Biochem Cell Biol. 2004;36(4):684–94.

    PubMed  CAS  Google Scholar 

  62. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.

    PubMed  CAS  Google Scholar 

  63. Chan SD, Karpf DB, Fowlkes ME, et al. Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem. 1992;267(35):25202–7.

    PubMed  CAS  Google Scholar 

  64. Lowry WE, Richter L. Signaling in adult stem cells. Front Biosci. 2007;12:3911–27.

    PubMed  CAS  Google Scholar 

  65. Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev. 1996;59(1):3–10.

    PubMed  CAS  Google Scholar 

  66. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59–88.

    PubMed  CAS  Google Scholar 

  67. Wagner TU. Bone morphogenetic protein signaling in stem cells–one signal, many consequences. FEBS J. 2007;274(12):2968–76.

    PubMed  CAS  Google Scholar 

  68. Kitisin K, Saha T, Blake T, et al. Tgf-Beta signaling in development. Sci STKE. 2007;2007(399):cm1.

    Google Scholar 

  69. Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2004;16(3):291–9.

    PubMed  CAS  Google Scholar 

  70. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.

    PubMed  CAS  Google Scholar 

  71. Mohr OL. Character changes caused by mutation of an entire region of a chromosome in Drosophila. Genetics. 1919;4(3): 275–82.

    PubMed  CAS  Google Scholar 

  72. Carlson ME, Conboy IM. Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol. 2007;7(3):303–9.

    PubMed  CAS  Google Scholar 

  73. Chiba S. Notch signaling in stem cell systems. Stem Cells. 2006;24(11):2437–47.

    PubMed  CAS  Google Scholar 

  74. Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007;194(3):459–74.

    PubMed  CAS  Google Scholar 

  75. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237–55.

    PubMed  CAS  Google Scholar 

  76. Gat U, DasGupta R, Degenstein L, Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. 1998;95(5):605–14.

    PubMed  CAS  Google Scholar 

  77. Silva-Vargas V, Lo Celso C, Giangreco A, et al. Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell. 2005;9(1):121–31.

    PubMed  CAS  Google Scholar 

  78. Jacob L, Lum L. Hedgehog signaling pathway. Sci STKE. 2007;2007(407):cm6.

    Google Scholar 

  79. Riobo NA, Manning DR. Pathways of signal transduction employed by vertebrate Hedgehogs. Biochem J. 2007;403(3): 369–79.

    PubMed  CAS  Google Scholar 

  80. Wright NA. Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer. Int J Exp Pathol. 2000;81(2):117–43.

    PubMed  CAS  Google Scholar 

  81. Winton DJ. Stem cells in the epithelium of the small intestine and colon. In: Marshak DR, Gardner RL, Gottlieb D, editors. Stem cell biology. Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press; 2001. pp. 515–36.

    Google Scholar 

  82. Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990;110(4):1001–20.

    PubMed  CAS  Google Scholar 

  83. Booth C, Potten CS. Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest. 2000;105(11):1493–9.

    PubMed  CAS  Google Scholar 

  84. He XC, Zhang J, Tong WG, et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet. 2004;36(10):1117–21.

    PubMed  CAS  Google Scholar 

  85. Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci. 2002;115(Pt 11):2381–8.

    PubMed  CAS  Google Scholar 

  86. Bjerknes M, Cheng H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology. 1999;116(1):7–14.

    PubMed  CAS  Google Scholar 

  87. Winton DJ, Blount MA, Ponder BA. A clonal marker induced by mutation in mouse intestinal epithelium. Nature. 1988;333(6172):463–6.

    PubMed  CAS  Google Scholar 

  88. Sancho E, Batlle E, Clevers H. Live and let die in the intestinal epithelium. Curr Opin Cell Biol. 2003;15(6):763–70.

    PubMed  CAS  Google Scholar 

  89. Garabedian EM, Roberts LJ, McNevin MS, Gordon JI. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J Biol Chem. 1997;272(38):23729–40.

    PubMed  CAS  Google Scholar 

  90. Giannakis M, Stappenbeck TS, Mills JC, et al. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem. 2006;281(16):11292–300.

    PubMed  CAS  Google Scholar 

  91. Wong MH, Saam JR, Stappenbeck TS, Rexer CH, Gordon JI. Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection. Proc Natl Acad Sci U S A. 2000;97(23):12601–6.

    PubMed  CAS  Google Scholar 

  92. Potten CS, Owen G, Roberts SA. The temporal and spatial changes in cell proliferation within the irradiated crypts of the murine small intestine. Int J Radiat Biol. 1990;57(1):185–99.

    PubMed  CAS  Google Scholar 

  93. Kim KM, Shibata D. Methylation reveals a niche: stem cell succession in human colon crypts. Oncogene. 2002;21(35):5441–9.

    PubMed  CAS  Google Scholar 

  94. Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001;293(5528):293–7.

    PubMed  CAS  Google Scholar 

  95. Karlsson L, Lindahl P, Heath JK, Betsholtz C. Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development. 2000;127(16):3457–66.

    PubMed  CAS  Google Scholar 

  96. Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19(4):379–83.

    PubMed  CAS  Google Scholar 

  97. Pinto D, Gregorieff A, Begthel H, Clevers H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17(14):1709–13.

    PubMed  CAS  Google Scholar 

  98. Kullander K, Klein R. Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol. 2002;3(7):475–86.

    PubMed  CAS  Google Scholar 

  99. Batlle E, Bacani J, Begthel H, et al. EphB receptor activity suppresses colorectal cancer progression. Nature. 2005;435(7045):1126–30.

    PubMed  CAS  Google Scholar 

  100. Holmberg J, Genander M, Halford MM, et al. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell. 2006;125(6):1151–63.

    PubMed  CAS  Google Scholar 

  101. Haramis AP, Begthel H, van den Born M, et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004;303(5664):1684–6.

    PubMed  CAS  Google Scholar 

  102. Takaku K, Miyoshi H, Matsunaga A, Oshima M, Sasaki N, Taketo MM. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 1999;59(24):6113–7.

    PubMed  CAS  Google Scholar 

  103. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 2001;294(5549):2155–8.

    PubMed  CAS  Google Scholar 

  104. Jensen J, Pedersen EE, Galante P, et al. Control of endodermal endocrine development by Hes-1. Nat Genet. 2000;24(1):36–44.

    PubMed  CAS  Google Scholar 

  105. Suzuki K, Fukui H, Kayahara T, et al. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. Biochem Biophys Res Commun. 2005;328(1):348–52.

    PubMed  CAS  Google Scholar 

  106. Schroder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns. 2002;2(3–4):247–50.

    PubMed  CAS  Google Scholar 

  107. Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S. Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005;435(7044):964–8.

    PubMed  CAS  Google Scholar 

  108. van Es JH, van Gijn ME, Riccio O, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435(7044):959–63.

    PubMed  Google Scholar 

  109. Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development. 2005;132(2):279–89.

    PubMed  CAS  Google Scholar 

  110. Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127(12):2763–72.

    PubMed  CAS  Google Scholar 

  111. van den Brink GR, Bleuming SA, Hardwick JC, et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet. 2004;36(3):277–82.

    PubMed  Google Scholar 

  112. Revoltella RP, Papini S, Rosellini A, Michelini M. Epithelial stem cells of the eye surface. Cell Prolif. 2007;40(4):445–61.

    PubMed  CAS  Google Scholar 

  113. Charukamnoetkanok P. Corneal stem cells: bridging the knowledge gap. Semin Ophthalmol. 2006;21(1):1–7.

    PubMed  CAS  Google Scholar 

  114. Dua HS, Forrester JV. The corneoscleral limbus in human corneal epithelial wound healing. Am J Ophthalmol. 1990;110(6): 646–56.

    PubMed  CAS  Google Scholar 

  115. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nature. 1971;229(5286):560–1.

    PubMed  CAS  Google Scholar 

  116. Miller SJ, Lavker RM, Sun TT. Keratinocyte stem cells of cornea, skin and hair follicles. In: Potten CS, editor. Stem cells. New York: Academic Press; 1997:331–62.

    Google Scholar 

  117. Schlotzer-Schrehardt U, Kruse FE. Identification and characterization of limbal stem cells. Exp Eye Res. 2005;81(3):247–64.

    PubMed  Google Scholar 

  118. Dua HS, Shanmuganathan VA, Powell-Richards AO, Tighe PJ, Joseph A. Limbal epithelial crypts: a novel anatomical structure and a putative limbal stem cell niche. Br JOphthalmol. 2005;89(5):529–32.

    CAS  Google Scholar 

  119. Dua HS, Joseph A, Shanmuganathan VA, Jones RE. Stem cell differentiation and the effects of deficiency. Eye. 2003;17(8): 877–85.

    PubMed  CAS  Google Scholar 

  120. Notara M, Daniels JT. Biological principals and clinical potentials of limbal epithelial stem cells. Cell Tissue Res. 2008;331(1): 135–43.

    PubMed  Google Scholar 

  121. Li W, Hayashida Y, Chen YT, Tseng SC. Niche regulation of corneal epithelial stem cells at the limbus. Cell Res. 2007;17(1):26–36.

    PubMed  Google Scholar 

  122. Higa K, Shimmura S, Miyashita H, Shimazaki J, Tsubota K. Melanocytes in the corneal limbus interact with K19-positive basal epithelial cells. Exp Eye Res. 2005;81(2):218–23.

    PubMed  CAS  Google Scholar 

  123. Narisawa Y, Kohda H, Tanaka T. Three-dimensional demonstration of melanocyte distribution of human hair follicles: special reference to the bulge area. Acta Dermato Venereol 1997;77(2): 97–101.

    CAS  Google Scholar 

  124. Espana EM, Kawakita T, Romano A, et al. Stromal niche controls the plasticity of limbal and corneal epithelial differentiation in a rabbit model of recombined tissue. Invest Ophthalmol Vis Sci. 2003;44(12):5130–5.

    PubMed  Google Scholar 

  125. Kawakita T, Espana EM, He H, Li W, Liu CY, Tseng SC. Intrastromal invasion by limbal epithelial cells is mediated by epithelial-mesenchymal transition activated by air exposure. Am J Pathol. 2005;167(2):381–93.

    PubMed  Google Scholar 

  126. Li DQ, Tseng SC. Three patterns of cytokine expression potentially involved in epithelial-fibroblast interactions of human ocular surface. J Cell Physiol 1995;163(1):61–79.

    PubMed  CAS  Google Scholar 

  127. Lovicu FJ, Kao WW, Overbeek PA. Ectopic gland induction by lens-specific expression of keratinocyte growth factor (FGF-7) in transgenic mice. Mech Dev. 1999;88(1):43–53.

    PubMed  CAS  Google Scholar 

  128. Touhami A, Grueterich M, Tseng SC. The role of NGF signaling in human limbal epithelium expanded by amniotic membrane culture. Invest Ophthalmol Vis Sci. 2002;43(4):987–94.

    PubMed  Google Scholar 

  129. Qi H, Chuang EY, Yoon KC, et al. Patterned expression of neurotrophic factors and receptors in human limbal and corneal regions. Mol Vis. 2007;13:1934–41.

    PubMed  CAS  Google Scholar 

  130. Fokina VM, Frolova EI. Expression patterns of Wnt genes during development of an anterior part of the chicken eye. Dev Dyn. 2006;235(2):496–505.

    PubMed  CAS  Google Scholar 

  131. Jin EJ, Burrus LW, Erickson CA. The expression patterns of Wnts and their antagonists during avian eye development. Mech Dev. 2002;116(1–2):173–6.

    PubMed  CAS  Google Scholar 

  132. Lyu J, Joo CK. Expression of Wnt and MMP in epithelial cells during corneal wound healing. Cornea. 2006;25(10 Suppl 1): S24–8.

    PubMed  Google Scholar 

  133. Pearton DJ, Yang Y, Dhouailly D. Transdifferentiation of corneal epithelium into epidermis occurs by means of a multistep process triggered by dermal developmental signals. Proc Natl Acad Sci U S A. 2005;102(10):3714–9.

    PubMed  CAS  Google Scholar 

  134. Mukhopadhyay M, Gorivodsky M, Shtrom S, et al. Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium. Development. 2006;133(11):2149–54.

    PubMed  CAS  Google Scholar 

  135. You L, Kruse FE, Pohl J, Volcker HE. Bone morphogenetic proteins and growth and differentiation factors in the human cornea. Invest Ophthalmol Vis Sci. 1999;40(2):296–311.

    PubMed  CAS  Google Scholar 

  136. Chang B, Smith RS, Peters M, et al. Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure. BMC Genet. 2001;2:18.

    PubMed  CAS  Google Scholar 

  137. Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416–21.

    PubMed  CAS  Google Scholar 

  138. Umemoto T, Yamato M, Nishida K, et al. Rat limbal epithelial side population cells exhibit a distinct expression of stem cell markers that are lacking in side population cells from the central cornea. FEBS Lett. 2005;579(29):6569–74.

    PubMed  CAS  Google Scholar 

  139. Thomas PB, Liu YH, Zhuang FF, et al. Identification of Notch-1 expression in the limbal basal epithelium. Mol Vis. 2007;13: 337–44.

    PubMed  CAS  Google Scholar 

  140. Ma A, Boulton M, Zhao B, Connon C, Cai J, Albon J. A role for notch signaling in human corneal epithelial cell differentiation and proliferation. Invest Ophthalmol Vis Sci. 2007;48(8): 3576–85.

    PubMed  Google Scholar 

  141. Saika S, Muragaki Y, Okada Y, et al. Sonic hedgehog expression and role in healing corneal epithelium. Invest Ophthalmol Vis Sci. 2004;45(8):2577–85.

    PubMed  Google Scholar 

  142. Takabatake T, Ogawa M, Takahashi TC, Mizuno M, Okamoto M, Takeshima K. Hedgehog and patched gene expression in adult ocular tissues. FEBS Lett. 1997;410(2–3):485–9.

    PubMed  CAS  Google Scholar 

  143. Richert MM, Schwertfeger KL, Ryder JW, Anderson SM. An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia. 2000;5(2):227–41.

    PubMed  CAS  Google Scholar 

  144. Kalirai H, Clarke RB. Human breast epithelial stem cells and their regulation. J Pathol. 2006;208(1):7–16.

    PubMed  CAS  Google Scholar 

  145. Vaillant F, Asselin-Labat ML, Shackleton M, Lindeman GJ, Visvader JE. The emerging picture of the mouse mammary stem cell. Stem Cell Rev. 2007;3(2):114–23.

    PubMed  Google Scholar 

  146. Williams JM, Daniel CW. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev Biol. 1983;97(2):274–90.

    PubMed  CAS  Google Scholar 

  147. Humphreys RC, Krajewska M, Krnacik S, et al. Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis. Development. 1996;122(12):4013–22.

    PubMed  CAS  Google Scholar 

  148. Smith GH, Chepko G. Mammary epithelial stem cells. Microsc Res Tech. 2001;52(2):190–203.

    PubMed  CAS  Google Scholar 

  149. Chepko G, Smith GH. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell. 1997;29(2):239–53.

    PubMed  CAS  Google Scholar 

  150. Chepko G, Dickson RB. Ultrastructure of the putative stem cell niche in rat mammary epithelium. Tissue Cell. 2003;35(2): 83–93.

    PubMed  CAS  Google Scholar 

  151. Smith GH. Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat. 1996;39(1):21–31.

    PubMed  CAS  Google Scholar 

  152. Alvi AJ, Clayton H, Joshi C, et al. Functional and molecular characterisation of mammary side population cells. Breast Cancer Res. 2003;5(1):R1–8.

    PubMed  Google Scholar 

  153. Welm B, Behbod F, Goodell MA, Rosen JM. Isolation and characterization of functional mammary gland stem cells. Cell Prolif. 2003;36 Suppl 1:17–32.

    PubMed  CAS  Google Scholar 

  154. Kordon EC, Smith GH. An entire functional mammary gland may comprise the progeny from a single cell. Development. 1998;125(10):1921–30.

    PubMed  CAS  Google Scholar 

  155. Stingl J, Eirew P, Ricketson I, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439(7079):993–7.

    PubMed  CAS  Google Scholar 

  156. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8.

    PubMed  CAS  Google Scholar 

  157. Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17(10):1253–70.

    PubMed  CAS  Google Scholar 

  158. Liao MJ, Zhang CC, Zhou B, et al. Enrichment of a population of mammary gland cells that form mammospheres and have in vivo repopulating activity. Cancer Res. 2007;67(17):8131–8.

    PubMed  CAS  Google Scholar 

  159. Parmar H, Cunha GR. Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocr-Relat Cancer. 2004;11(3):437–58.

    PubMed  CAS  Google Scholar 

  160. Turashvili G, Bouchal J, Burkadze G, Kolar Z. Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73(5):213–23.

    PubMed  CAS  Google Scholar 

  161. van Genderen C, Okamura RM, Farinas I, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 1994;8(22):2691–703.

    PubMed  Google Scholar 

  162. Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell. 2002;2(5):643–53.

    PubMed  CAS  Google Scholar 

  163. Tepera SB, McCrea PD, Rosen JM. A beta-catenin survival signal is required for normal lobular development in the mammary gland. J Cell Sci. 2003;116(Pt 6):1137–49.

    PubMed  CAS  Google Scholar 

  164. Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci U S A. 2004;101(12):4158–63.

    PubMed  CAS  Google Scholar 

  165. Teuliere J, Faraldo MM, Deugnier MA, et al. Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia. Development. 2005;132(2):267–77.

    PubMed  CAS  Google Scholar 

  166. Alexander CM, Reichsman F, Hinkes MT, et al. Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Nat Genet. 2000;25(3):329–32.

    PubMed  CAS  Google Scholar 

  167. Smith GH, Gallahan D, Diella F, Jhappan C, Merlino G, Callahan R. Constitutive expression of a truncated INT3 gene in mouse mammary epithelium impairs differentiation and functional development. Cell Growth Differ. 1995;6(5):563–77.

    PubMed  CAS  Google Scholar 

  168. Callahan R, Egan SE. Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia. 2004;9(2):145–63.

    PubMed  Google Scholar 

  169. Gallahan D, Jhappan C, Robinson G, et al. Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis. Cancer Res. 1996;56(8):1775–85.

    PubMed  CAS  Google Scholar 

  170. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605–15.

    PubMed  CAS  Google Scholar 

  171. Lewis MT. Hedgehog signaling in mouse mammary gland development and neoplasia. J Mammary Gland Biol Neoplasia. 2001;6(1):53–66.

    PubMed  CAS  Google Scholar 

  172. Lewis MT, Ross S, Strickland PA, et al. The Gli2 transcription factor is required for normal mouse mammary gland development. Dev Biol. 2001;238(1):133–44.

    PubMed  CAS  Google Scholar 

  173. Lewis MT, Ross S, Strickland PA, et al. Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. Development. 1999;126(22):5181–93.

    PubMed  CAS  Google Scholar 

  174. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66(12):6063–71.

    PubMed  CAS  Google Scholar 

  175. Kubo M, Nakamura M, Tasaki A, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res. 2004;64(17):6071–4.

    PubMed  CAS  Google Scholar 

  176. Dooley J, Erickson M, Roelink H, Farr AG. Nude thymic rudiment lacking functional foxn1 resembles respiratory epithelium. Dev Dyn. 2005;233(4):1605–12.

    PubMed  CAS  Google Scholar 

  177. Patel DD, Whichard LP, Radcliff G, Denning SM, Haynes BF. Characterization of human thymic epithelial cell surface antigens: phenotypic similarity of thymic epithelial cells to epidermal keratinocytes. J Clin Immunol. 1995;15(2):80–92.

    PubMed  CAS  Google Scholar 

  178. Lobach DF, Haynes BF. Ontogeny of the human thymus during fetal development. JClinImmunol. 1987;7(2):81–97.

    CAS  Google Scholar 

  179. Laster AJ, Itoh T, Palker TJ, Haynes BF. The human thymic microenvironment: thymic epithelium contains specific keratins associated with early and late stages of epidermal keratinocyte maturation. Differentiation. 1986;31(1):67–77.

    PubMed  CAS  Google Scholar 

  180. Nishio H, Matsui K, Tsuji H, Tamura A, Suzuki K. Immunolocalization of calcineurin and FKBP12, the FK506-binding protein, in Hassall’s corpuscles of human thymus and epidermis. Histochem Cell Biol. 2000;114(1):9–14.

    PubMed  CAS  Google Scholar 

  181. Senoo M, Pinto F, Crum CP, McKeon F. p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia. Cell. 2007;129(3):523–36.

    PubMed  CAS  Google Scholar 

  182. Khlystova ZS, Kalinina, II, Khavinson V. Thymic hormones in human fetal skin epidermis. Bull Exp Biol Med. 2002;133(2):196–8.

    PubMed  CAS  Google Scholar 

  183. Rossi SW, Chidgey AP, Parnell SM, et al. Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol. 2007;37(9):2411–8.

    PubMed  CAS  Google Scholar 

  184. Gill J, Malin M, Hollander GA, Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol. 2002;3(7):635–42.

    PubMed  CAS  Google Scholar 

  185. Nijhof JG, van Pelt C, Mulder AA, Mitchell DL, Mullenders LH, de Gruijl FR. Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency. Carcinogenesis. 2007;28(4):792–800.

    PubMed  CAS  Google Scholar 

  186. Trempus CS, Morris RJ, Ehinger M, et al. CD34 expression by hair follicle stem cells is required for skin tumor development in mice. Cancer Res. 2007;67(9):4173–81.

    PubMed  CAS  Google Scholar 

  187. Nijhof JG, Braun KM, Giangreco A, et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development. 2006;133(15):3027–37.

    PubMed  CAS  Google Scholar 

  188. Blackburn CC, Augustine CL, Li R, et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci U S A. 1996;93(12):5742–6.

    PubMed  CAS  Google Scholar 

  189. Nehls M, Kyewski B, Messerle M, et al. Two genetically separable steps in the differentiation of thymic epithelium. Science. 1996;272(5263):886–9.

    PubMed  CAS  Google Scholar 

  190. Mecklenburg L, Tychsen B, Paus R. Learning from nudity: lessons from the nude phenotype. Exp Dermatol. 2005;14(11):797–810.

    PubMed  CAS  Google Scholar 

  191. Clark RA, Yamanaka K, Bai M, Dowgiert R, Kupper TS. Human skin cells support thymus-independent T cell development. J Clin Invest. 2005;115(11):3239–49.

    PubMed  CAS  Google Scholar 

  192. Braun KM, Prowse DM. Distinct epidermal stem cell compartments are maintained by independent niche microenvironments. Stem Cell Rev. 2006;2(3):221–31.

    PubMed  CAS  Google Scholar 

  193. Chuong C-M. Morphogenesis of epithelial appendages: variations on top of a common theme and implications in regeneration. In: Chuong C-M, editor. Molecular basis of epithelial appendage morphogenesis. Austin: R.G. Landes Company; 1998. pp. 3–14.

    Google Scholar 

  194. Mikkola ML. Genetic basis of skin appendage development. Semin Cell Dev Biol. 2007;18(2):225–36.

    PubMed  CAS  Google Scholar 

  195. Koster MI, Roop DR. Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol. 2007;23:93–113.

    PubMed  CAS  Google Scholar 

  196. Wilson SI, Rydstrom A, Trimborn T, et al. The status of Wnt signalling regulates neural and epidermal fates in the chick embryo. Nature. 2001;411(6835):325–30.

    PubMed  CAS  Google Scholar 

  197. Mack JA, Anand S, Maytin EV. Proliferation and cornification during development of the mammalian epidermis. Birth Defects Res C Embryo Today. 2005;75(4):314–29.

    PubMed  CAS  Google Scholar 

  198. Blanpain C, Fuchs E. Epidermal stem cells of the skin. Annu Rev Cell Dev Biol. 2006;22:339–73.

    PubMed  CAS  Google Scholar 

  199. Byrne C, Tainsky M, Fuchs E. Programming gene expression in developing epidermis. Development. 1994;120(9):2369–83.

    PubMed  CAS  Google Scholar 

  200. Armstrong MT, Turlo K, Elges CJ, Dayton SM, Lee J, Armstrong PB. A novel form of epithelial wound healing of the embryonic epidermis. Exp Cell Res. 2006;312(13):2415–23.

    PubMed  CAS  Google Scholar 

  201. M’Boneko V, Merker HJ. Development and morphology of the periderm of mouse embryos (days 9–12 of gestation). Acta Anat. 1988;133(4):325–36.

    PubMed  Google Scholar 

  202. Koster MI, Dai D, Marinari B, et al. p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci U S A. 2007;104(9):3255–60.

    PubMed  CAS  Google Scholar 

  203. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev. 2005;6(4):328–40.

    CAS  Google Scholar 

  204. Hardman MJ, Sisi P, Banbury DN, Byrne C. Patterned acquisition of skin barrier function during development. Development. 1998;125(8):1541–52.

    PubMed  CAS  Google Scholar 

  205. Segre J. Complex redundancy to build a simple epidermal permeability barrier. Curr Opin Cell Biol. 2003;15(6):776–82.

    PubMed  CAS  Google Scholar 

  206. Koster MI, Roop DR. Genetic pathways required for epidermal morphogenesis. Eur J Cell Biol. 2004;83(11–12):625–9.

    PubMed  Google Scholar 

  207. Schmidt-Ullrich R, Paus R. Molecular principles of hair follicle induction and morphogenesis. Bioessays. 2005;27(3):247–61.

    PubMed  CAS  Google Scholar 

  208. Waters JM, Richardson GD, Jahoda CA. Hair follicle stem cells. Semin Cell Dev Biol. 2007;18(2):245–54.

    PubMed  CAS  Google Scholar 

  209. Fuchs E. Scratching the surface of skin development. Nature. 2007;445(7130):834–42.

    PubMed  CAS  Google Scholar 

  210. Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118(2):216–25.

    PubMed  CAS  Google Scholar 

  211. Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ. Hair follicle pigmentation. J Invest Dermatol. 2005;124(1):13–21.

    PubMed  CAS  Google Scholar 

  212. Barsh G, Cotsarelis G. How hair gets its pigment. Cell. 2007;130(5):779–81.

    PubMed  CAS  Google Scholar 

  213. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84(4):1155–228.

    PubMed  CAS  Google Scholar 

  214. Webb A, Kaur P. Epidermal stem cells. Front Biosci. 2006; 11:1031–41.

    PubMed  CAS  Google Scholar 

  215. Potten CS. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 1974;7(1):77–88.

    PubMed  CAS  Google Scholar 

  216. Potten CS. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int Rev Cytol. 1981;69:271–318.

    PubMed  CAS  Google Scholar 

  217. Braun KM, Niemann C, Jensen UB, Sundberg JP, Silva-Vargas V, Watt FM. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development. 2003;130(21): 5241–55.

    PubMed  CAS  Google Scholar 

  218. Ghazizadeh S, Taichman LB. Organization of stem cells and their progeny in human epidermis. J Invest Dermatol. 2005;124(2):367–72.

    PubMed  CAS  Google Scholar 

  219. Lavker RM, Sun TT. Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci U S A. 2000;97(25):13473–5.

    PubMed  CAS  Google Scholar 

  220. Kaur P. Interfollicular epidermal stem cells: identification, challenges, potential. J Invest Dermatol. 2006;126(7):1450–8.

    PubMed  CAS  Google Scholar 

  221. Jensen UB, Lowell S, Watt FM. The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development. 1999;126(11):2409–18.

    PubMed  CAS  Google Scholar 

  222. Jones PH, Harper S, Watt FM. Stem cell patterning and fate in human epidermis. Cell. 1995;80(1):83–93.

    PubMed  CAS  Google Scholar 

  223. Lavker RM, Sun TT. Epidermal stem cells. J Invest Dermatol. 1983;81(1 Suppl):121s–7s.

    PubMed  CAS  Google Scholar 

  224. Webb A, Li A, Kaur P. Location and phenotype of human adult keratinocyte stem cells of the skin. Differentiation. 2004;72(8):387–95.

    PubMed  Google Scholar 

  225. Wan H, Stone MG, Simpson C, et al. Desmosomal proteins, including desmoglein 3, serve as novel negative markers for epidermal stem cell-containing population of keratinocytes. J Cell Sci. 2003;116(Pt 20):4239–48.

    PubMed  CAS  Google Scholar 

  226. Legg J, Jensen UB, Broad S, Leigh I, Watt FM. Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Development. 2003;130(24): 6049–63.

    PubMed  CAS  Google Scholar 

  227. Ito M, Yang Z, Andl T, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447(7142):316–20.

    PubMed  CAS  Google Scholar 

  228. Ghazizadeh S, Taichman LB. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 2001;20(6):1215–22.

    PubMed  CAS  Google Scholar 

  229. Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol. 2006;126(7):1459–68.

    PubMed  CAS  Google Scholar 

  230. Moll I. Differential epithelial outgrowth of plucked and microdissected human hair follicles in explant culture. Arch Dermatol Res. 1996;288(10):604–10.

    PubMed  CAS  Google Scholar 

  231. Rochat A, Kobayashi K, Barrandon Y. Location of stem cells of human hair follicles by clonal analysis. Cell. 1994;76(6):1063–73.

    PubMed  CAS  Google Scholar 

  232. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329–37.

    PubMed  CAS  Google Scholar 

  233. Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;102(4):451–61.

    PubMed  CAS  Google Scholar 

  234. Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104(2):233–45.

    PubMed  CAS  Google Scholar 

  235. Weinberg WC, Goodman LV, George C, et al. Reconstitution of hair follicle development in vivo: determination of follicle formation, hair growth, and hair quality by dermal cells. J Invest Dermatol. 1993;100(3):229–36.

    PubMed  CAS  Google Scholar 

  236. Levy V, Lindon C, Harfe BD, Morgan BA. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell. 2005;9(6):855–61.

    PubMed  CAS  Google Scholar 

  237. Ito M, Liu Y, Yang Z, et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351–4.

    PubMed  CAS  Google Scholar 

  238. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303(5656):359–63.

    PubMed  CAS  Google Scholar 

  239. Li L, Mignone J, Yang M, et al. Nestin expression in hair follicle sheath progenitor cells. Proc Natl Acad Sci U S A. 2003;100(17):9958–61.

    PubMed  CAS  Google Scholar 

  240. Amoh Y, Li L, Katsuoka K, Penman S, Hoffman RM. Multipotent nestin-positive, keratin-negative hair-follicle bulge stem cells can form neurons. Proc Natl Acad Sci U S A. 2005;102(15): 5530–4.

    PubMed  CAS  Google Scholar 

  241. Amoh Y, Li L, Yang M, et al. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci U S A. 2004;101(36):13291–5.

    PubMed  CAS  Google Scholar 

  242. Amoh Y, Li L, Campillo R, et al. Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves. Proc Natl Acad Sci U S A. 2005;102(49):17734–8.

    PubMed  CAS  Google Scholar 

  243. Hoffman RM. The pluripotency of hair follicle stem cells. Cell Cycle. 2006;5(3):232–3.

    PubMed  CAS  Google Scholar 

  244. Tiede S, Kloepper JE, Bodo E, Tiwari S, Kruse C, Paus R. Hair follicle stem cells: walking the maze. Eur J Cell Biol. 2007;86(7):355–76.

    PubMed  CAS  Google Scholar 

  245. Morris RJ, Potten CS. Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J Invest Dermatol. 1999;112(4):470–5.

    PubMed  CAS  Google Scholar 

  246. Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis G. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci. 1998;111 (Pt 21):3179–88.

    PubMed  CAS  Google Scholar 

  247. Kaur P, Li A, Redvers R, Bertoncello I. Keratinocyte stem cell assays: an evolving science. J Investig Dermatol Symp Proc. 2004;9(3):238–47.

    PubMed  CAS  Google Scholar 

  248. Kobayashi K, Rochat A, Barrandon Y. Segregation of keratinocyte colony-forming cells in the bulge of the rat vibrissa. Proc Natl Acad Sci U S A. 1993;90(15):7391–5.

    PubMed  CAS  Google Scholar 

  249. Morris RJ, Liu Y, Marles L, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004;22(4):411–7.

    PubMed  CAS  Google Scholar 

  250. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest. 2006;116(1):249–60.

    PubMed  CAS  Google Scholar 

  251. Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci U S A. 1987;84(8):2302–6.

    PubMed  CAS  Google Scholar 

  252. Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989;245(4919):752–5.

    PubMed  CAS  Google Scholar 

  253. Kulessa H, Turk G, Hogan BL. Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle. EMBO J. 2000;19(24):6664–74.

    PubMed  CAS  Google Scholar 

  254. Botchkarev VA, Botchkareva NV, Roth W, et al. Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nat Cell Biol. 1999;1(3):158–64.

    PubMed  CAS  Google Scholar 

  255. Pummila M, Fliniaux I, Jaatinen R, et al. Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression. Development, 2007;134(1):117–25.

    PubMed  CAS  Google Scholar 

  256. Atit R, Sgaier SK, Mohamed OA, et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol. 2006;296(1):164–76.

    PubMed  CAS  Google Scholar 

  257. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105(4):533–45.

    PubMed  CAS  Google Scholar 

  258. Nguyen H, Rendl M, Fuchs E. Tcf3 governs stem cell features and represses cell fate determination in skin. Cell. 2006;127(1): 171–83.

    PubMed  CAS  Google Scholar 

  259. Merrill BJ, Gat U, DasGupta R, Fuchs E. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 2001;15(13):1688–705.

    PubMed  CAS  Google Scholar 

  260. DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development. 1999;126(20):4557–68.

    PubMed  CAS  Google Scholar 

  261. Xia J, Urabe K, Moroi Y, et al. beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas. J Dermatol Sci. 2006;41(1):67–75.

    PubMed  CAS  Google Scholar 

  262. Lo Celso C, Prowse DM, Watt FM. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development. 2004;131(8):1787–99.

    PubMed  CAS  Google Scholar 

  263. Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev. 2002;16(24):3173–85.

    PubMed  CAS  Google Scholar 

  264. Alonso L, Fuchs E. Stem cells in the skin: waste not, Wnt not. Genes Dev. 2003;17(10):1189–200.

    PubMed  CAS  Google Scholar 

  265. Botchkarev VA, Sharov AA. BMP signaling in the control of skin development and hair follicle growth. Differentiation. 2004;72(9–10):512–26.

    PubMed  CAS  Google Scholar 

  266. Nikaido M, Tada M, Takeda H, Kuroiwa A, Ueno N. In vivo analysis using variants of zebrafish BMPR-IA: range of action and involvement of BMP in ectoderm patterning. Development. 1999;126(1):181–90.

    PubMed  CAS  Google Scholar 

  267. Botchkarev VA, Botchkareva NV, Nakamura M, et al. Noggin is required for induction of the hair follicle growth phase in postnatal skin. FASEB J. 2001;15(12):2205–14.

    PubMed  CAS  Google Scholar 

  268. Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc Natl Acad Sci U S A. 2007;104(24):10063–8.

    PubMed  CAS  Google Scholar 

  269. Andl T, Ahn K, Kairo A, et al. Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development. Development. 2004;131(10):2257–68.

    PubMed  CAS  Google Scholar 

  270. Chiang C, Swan RZ, Grachtchouk M, et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol. 1999;205(1):1–9.

    PubMed  CAS  Google Scholar 

  271. Oro AE, Higgins K. Hair cycle regulation of Hedgehog signal reception. Dev Biol. 2003;255(2):238–48.

    PubMed  CAS  Google Scholar 

  272. St-Jacques B, Dassule HR, Karavanova I, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol. 1998;8(19):1058–68.

    PubMed  CAS  Google Scholar 

  273. Mill P, Mo R, Fu H, et al. Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development. Genes Dev. 2003;17(2):282–94.

    PubMed  CAS  Google Scholar 

  274. Adolphe C, Narang M, Ellis T, Wicking C, Kaur P, Wainwright B. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development. 2004;131(20):5009–19.

    PubMed  CAS  Google Scholar 

  275. Niemann C, Unden AB, Lyle S, Zouboulis Ch C, Toftgard R, Watt FM. Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis. Proc Natl Acad Sci U S A. 2003;100 Suppl 1:11873–80.

    PubMed  CAS  Google Scholar 

  276. Blanpain C, Lowry WE, Pasolli HA, Fuchs E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 2006;20(21):3022–35.

    PubMed  CAS  Google Scholar 

  277. Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001;20(13):3427–36.

    PubMed  CAS  Google Scholar 

  278. Okuyama R, Nguyen BC, Talora C, et al. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell. 2004;6(4):551–62.

    PubMed  CAS  Google Scholar 

  279. Pan Y, Lin MH, Tian X, et al. gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell. 2004;7(5):731–43.

    PubMed  CAS  Google Scholar 

  280. Vauclair S, Nicolas M, Barrandon Y, Radtke F. Notch1 is essential for postnatal hair follicle development and homeostasis. Dev Biol. 2005;284(1):184–93.

    PubMed  CAS  Google Scholar 

  281. Yamamoto N, Tanigaki K, Han H, Hiai H, Honjo T. Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Curr Biol. 2003;13(4):333–8.

    PubMed  CAS  Google Scholar 

  282. Kopan R, Weintraub H. Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol. 1993;121(3):631–41.

    PubMed  CAS  Google Scholar 

  283. Jensen KB, Watt FM. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc Natl Acad Sci U S A. 2006;103(32):11958–63.

    PubMed  CAS  Google Scholar 

  284. Rhee H, Polak L, Fuchs E. Lhx2 maintains stem cell character in hair follicles. Science. 2006;312(5782):1946–9.

    PubMed  CAS  Google Scholar 

  285. Benitah SA, Frye M, Glogauer M, Watt FM. Stem cell depletion through epidermal deletion of Rac1. Science. 2005;309(5736):933–5.

    PubMed  Google Scholar 

  286. Benitah SA, Watt FM. Epidermal deletion of Rac1 causes stem cell depletion, irrespective of whether deletion occurs during embryogenesis or adulthood. J Invest Dermatol. 2007;127(6): 1555–7.

    PubMed  CAS  Google Scholar 

  287. Chrostek A, Wu X, Quondamatteo F, et al. Rac1 is crucial for hair follicle integrity but is not essential for maintenance of the epidermis. Mol Cell Biol. 2006;26(18):6957–70.

    PubMed  CAS  Google Scholar 

  288. Castilho RM, Squarize CH, Patel V, et al. Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells. Oncogene. 2007;26(35):5078–85.

    PubMed  CAS  Google Scholar 

  289. Green H. Terminal differentiation of cultured human epidermal cells. Cell. 1977;11(2):405–16.

    PubMed  CAS  Google Scholar 

  290. Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975;6(3):331–43.

    PubMed  CAS  Google Scholar 

  291. O’Connor NE, Mulliken JB, Banks-Schlegel S, Kehinde O, Green H. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet. 1981;1(8211):75–8.

    Google Scholar 

  292. Pellegrini G, Ranno R, Stracuzzi G, et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation. 1999;68(6):868–79.

    PubMed  CAS  Google Scholar 

  293. Ronfard V, Rives JM, Neveux Y, Carsin H, Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation. 2000;70(11):1588–98.

    PubMed  CAS  Google Scholar 

  294. Burd A, Ahmed K, Lam S, Ayyappan T, Huang L. Stem cell strategies in burns care. Burns. 2007;33(3):282–91.

    PubMed  CAS  Google Scholar 

  295. Boyd RL, Tucek CL, Godfrey DI, et al. The thymic microenvironment. Immunol Today. 1993;14(9):445–59.

    PubMed  CAS  Google Scholar 

  296. Gordon J, Wilson VA, Blair NF, et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol. 2004;5(5):546–53.

    PubMed  CAS  Google Scholar 

  297. Itoi M, Tsukamoto N, Yoshida H, Amagai T. Mesenchymal cells are required for functional development of thymic epithelial cells. Int Immunol. 2007;19(8):953–64.

    PubMed  CAS  Google Scholar 

  298. Klug DB, Carter C, Gimenez-Conti IB, Richie ER. Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol. 2002;169(6):2842–5.

    PubMed  CAS  Google Scholar 

  299. Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1(1):31–40.

    PubMed  CAS  Google Scholar 

  300. van Ewijk W, Hollander G, Terhorst C, Wang B. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development. 2000;127(8):1583–91.

    PubMed  Google Scholar 

  301. Muller SM, Terszowski G, Blum C, et al. Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc Natl Acad Sci U S A. 2005;102(30):10587–92.

    PubMed  Google Scholar 

  302. Hollander G, Gill J, Zuklys S, Iwanami N, Liu C, Takahama Y. Cellular and molecular events during early thymus development. Immunol Rev. 2006;209:28–46.

    PubMed  CAS  Google Scholar 

  303. Nowell CS, Farley AM, Blackburn CC. Thymus organogenesis and development of the thymic stroma. Methods Mol Biol. 2007;380:125–62.

    PubMed  CAS  Google Scholar 

  304. Graham A. The development and evolution of the pharyngeal arches. J Anat. 2001;199(Pt 1–2):133–41.

    PubMed  CAS  Google Scholar 

  305. Graham A, Smith A. Patterning the pharyngeal arches. Bioessays. 2001;23(1):54–61.

    PubMed  CAS  Google Scholar 

  306. Schilling TF. Genetic analysis of craniofacial development in the vertebrate embryo. Bioessays. 1997;19(6):459–68.

    PubMed  CAS  Google Scholar 

  307. Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development. 1995;121(7):1989–2003.

    PubMed  CAS  Google Scholar 

  308. Manley NR. Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin Immunol. 2000;12(5):421–8.

    PubMed  CAS  Google Scholar 

  309. Gordon J, Bennett AR, Blackburn CC, Manley NR. Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev. 2001;103(1–2):141–3.

    PubMed  CAS  Google Scholar 

  310. Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol. 1975;34(1):125–54.

    PubMed  CAS  Google Scholar 

  311. Manley NR, Capecchi MR. Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev Biol. 1998;195(1):1–15.

    PubMed  CAS  Google Scholar 

  312. Blackburn CC, Manley NR. Developing a new paradigm for thymus organogenesis. Nat Rev Immunol. 2004;4(4):278–89.

    PubMed  CAS  Google Scholar 

  313. Haynes BF, Heinly CS. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med. 1995;181(4):1445–58.

    PubMed  CAS  Google Scholar 

  314. Bleul CC, Boehm T. Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol. 2000;30(12):3371–9.

    PubMed  CAS  Google Scholar 

  315. Liu C, Ueno T, Kuse S, et al. The role of CCL21 in recruitment of T-precursor cells to fetal thymi. Blood. 2005;105(1):31–9.

    PubMed  CAS  Google Scholar 

  316. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R. Thymic generation and regeneration. Immunol Rev. 2003;195: 28–50.

    PubMed  CAS  Google Scholar 

  317. Amagai T, Itoi M, Kondo Y. Limited development capacity of the earliest embryonic murine thymus. Eur J Immunol. 1995;25(3):757–62.

    PubMed  CAS  Google Scholar 

  318. van Ewijk W, Wang B, Hollander G, et al. Thymic microenvironments, 3-D versus 2-D? Semin Immunol. 1999;11(1):57–64.

    PubMed  Google Scholar 

  319. Guidos C. Thymus and T-lymphocyte development: what is new in the 21st century? Immunol Rev. 2006;209:5–9.

    PubMed  Google Scholar 

  320. van Dyke JH. On the origin of accessory thymus tissue, thymus IV: the occurrence in man. Anat Rec. 1941;79:179–209.

    Google Scholar 

  321. Tovi F, Mares AJ. The aberrant cervical thymus. Embryology, Pathology, and clinical implications. Am J Surg. 1978;136(5):631–7.

    PubMed  CAS  Google Scholar 

  322. Ashour M. Prevalence of ectopic thymic tissue in myasthenia gravis and its clinical significance. J Thorac Cardiovasc Surg. 1995;109(4):632–5.

    PubMed  CAS  Google Scholar 

  323. Dooley J, Erickson M, Gillard GO, Farr AG. Cervical thymus in the mouse. J Immunol. 2006;176(11):6484–90.

    PubMed  CAS  Google Scholar 

  324. Terszowski G, Muller SM, Bleul CC, et al. Evidence for a functional second thymus in mice. Science. 2006;312(5771):284–7.

    PubMed  CAS  Google Scholar 

  325. von Boehmer H. Immunology. Thoracic thymus, exclusive no longer. Science. 2006;312(5771):206–7.

    Google Scholar 

  326. Panigraphi D, Waxler GL, Mallman VH. The thymus in the chicken and its anatomical relationship to the thyroid. J Immunol. 1971;107(1):289–92.

    PubMed  CAS  Google Scholar 

  327. Manley NR, Blackburn CC. A developmental look at thymus organogenesis: where do the non-hematopoietic cells in the thymus come from? Curr Opin Immunol. 2003;15(2):225–32.

    PubMed  CAS  Google Scholar 

  328. Blackburn CC, Manley NR, Palmer DB, Boyd RL, Anderson G, Ritter MA. One for all and all for one: thymic epithelial stem cells and regeneration. Trends Immunol. 2002;23(8):391–5.

    PubMed  CAS  Google Scholar 

  329. Cordier AC, Heremans JF. Nude mouse embryo: ectodermal nature of the primordial thymic defect. Scand J Immunol. 1975;4(2):193–6.

    PubMed  CAS  Google Scholar 

  330. Cordier AC, Haumont SM. Development of thymus, parathyroids, and ultimo-branchial bodies in NMRI and nude mice. Am J Anat. 1980;157(3):227–63.

    PubMed  CAS  Google Scholar 

  331. Anderson G, Jenkinson WE, Jones T, et al. Establishment and functioning of intrathymic microenvironments. Immunol Rev. 2006;209:10–27.

    PubMed  Google Scholar 

  332. Le Douarin NM, Jotereau FV. Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J Exp Med. 1975;142(1):17–40.

    PubMed  CAS  Google Scholar 

  333. Suniara RK, Jenkinson EJ, Owen JJ. An essential role for thymic mesenchyme in early T cell development. J Exp Med. 2000;191(6):1051–6.

    PubMed  CAS  Google Scholar 

  334. Jenkinson WE, Rossi SW, Jenkinson EJ, Anderson G. Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech Dev. 2005;122(12):1294–9.

    PubMed  CAS  Google Scholar 

  335. Zhang L, Sun L, Zhao Y. Thymic epithelial progenitor cells and thymus regeneration: an update. Cell Res. 2007;17(1):50–5.

    PubMed  Google Scholar 

  336. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development. 2000;127(8):1607–16.

    PubMed  CAS  Google Scholar 

  337. Waldo KL, Kumiski D, Kirby ML. Cardiac neural crest is essential for the persistence rather than the formation of an arch artery. Dev Dyn. 1996;205(3):281–92.

    PubMed  CAS  Google Scholar 

  338. Bockman DE, Kirby ML. Dependence of thymus development on derivatives of the neural crest. Science. 1984;223(4635):498–500.

    PubMed  CAS  Google Scholar 

  339. Kirby ML, Waldo KL. Role of neural crest in congenital heart disease. Circulation. 1990;82(2):332–40.

    PubMed  CAS  Google Scholar 

  340. Kuratani S, Bockman DE. Impaired development of the thymic primordium after neural crest ablation. Anat Rec. 1990;228(2):185–90.

    PubMed  CAS  Google Scholar 

  341. Shinohara T, Honjo T. Studies in vitro on the mechanism of the epithelial/mesenchymal interaction in the early fetal thymus. Eur J Immunol. 1997;27(2):522–9.

    PubMed  CAS  Google Scholar 

  342. Shinohara T, Honjo T. Epidermal growth factor can replace thymic mesenchyme in induction of embryonic thymus morphogenesis in vitro. Eur J Immunol. 1996;26(4):747–52.

    PubMed  CAS  Google Scholar 

  343. Jenkinson WE, Rossi SW, Parnell SM, Jenkinson EJ, Anderson G. PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood. 2007;109(3):954–60.

    PubMed  CAS  Google Scholar 

  344. Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol. 2001;231(1):47–62.

    PubMed  CAS  Google Scholar 

  345. Dooley J, Erickson M, Larochelle WJ, Gillard GO, Farr AG. FGFR2IIIb signaling regulates thymic epithelial differentiation. Dev Dyn. 2007;236(12):3459–71.

    PubMed  CAS  Google Scholar 

  346. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J Immunol. 2001;167(4):1954–61.

    PubMed  CAS  Google Scholar 

  347. Gray DH, Tull D, Ueno T, et al. A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15. J Immunol. 2007;178(8):4956–65.

    PubMed  CAS  Google Scholar 

  348. van Ewijk W, Shores EW, Singer A. Crosstalk in the mouse thymus. Immunol Today. 1994;15(5):214–7.

    PubMed  Google Scholar 

  349. Ritter MA, Boyd RL. Development in the thymus: it takes two to tango. Immunol Today. 1993;14(9):462–9.

    PubMed  CAS  Google Scholar 

  350. Hollander GA, Wang B, Nichogiannopoulou A, et al. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature. 1995;373(6512):350–3.

    PubMed  CAS  Google Scholar 

  351. Palmer DB, Viney JL, Ritter MA, Hayday AC, Owen MJ. Expression of the alpha beta T-cell receptor is necessary for the generation of the thymic medulla. Dev Immunol. 1993;3(3):175–9.

    PubMed  CAS  Google Scholar 

  352. Shores EW, Van Ewijk W, Singer A. Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur J Immunol. 1991;21(7):1657–61.

    PubMed  CAS  Google Scholar 

  353. Shores EW, Van Ewijk W, Singer A. Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol. 1994;6(9):1393–402.

    PubMed  CAS  Google Scholar 

  354. Surh CD, Ernst B, Sprent J. Growth of epithelial cells in the thymic medulla is under the control of mature T cells. J Exp Med. 1992;176(2):611–6.

    PubMed  CAS  Google Scholar 

  355. Rodewald HR, Ogawa M, Haller C, Waskow C, DiSanto JP. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma chain is essential for repertoire formation. Immunity. 1997;6(3):265–72.

    PubMed  CAS  Google Scholar 

  356. Yarilin AA, Belyakov IM. Cytokines in the thymus: production and biological effects. Curr Med Chem. 2004;11(4):447–64.

    PubMed  CAS  Google Scholar 

  357. Boehm T, Scheu S, Pfeffer K, Bleul CC. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med. 2003;198(5):757–69.

    PubMed  CAS  Google Scholar 

  358. Venanzi ES, Gray DH, Benoist C, Mathis D. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol. 2007;179(9):5693–700.

    PubMed  CAS  Google Scholar 

  359. Rossi SW, Kim MY, Leibbrandt A, et al. RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007;204(6):1267–72.

    PubMed  CAS  Google Scholar 

  360. Iimura T, Pourquie O. Hox genes in time and space during vertebrate body formation. Dev Growth Differ. 2007;49(4):265–75.

    PubMed  CAS  Google Scholar 

  361. Svingen T, Tonissen KF. Hox transcription factors and their elusive mammalian gene targets. Heredity. 2006;97(2):88–96.

    PubMed  CAS  Google Scholar 

  362. Chisaka O, Kameda Y. Hoxa3 regulates the proliferation and differentiation of the third pharyngeal arch mesenchyme in mice. Cell Tissue Res. 2005;320(1):77–89.

    PubMed  CAS  Google Scholar 

  363. Chisaka O, Capecchi MR. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature. 1991;350(6318):473–9.

    PubMed  CAS  Google Scholar 

  364. Rossel M, Capecchi MR. Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development. 1999;126(22):5027–40.

    PubMed  CAS  Google Scholar 

  365. Mann RS, Affolter M. Hox proteins meet more partners. Curr Opin Genet Dev. 1998;8(4):423–9.

    PubMed  CAS  Google Scholar 

  366. Manley NR, Selleri L, Brendolan A, Gordon J, Cleary ML. Abnormalities of caudal pharyngeal pouch development in Pbx1 knockout mice mimic loss of Hox3 paralogs. Dev Biol. 2004;276(2):301–12.

    PubMed  CAS  Google Scholar 

  367. Lang D, Powell SK, Plummer RS, Young KP, Ruggeri BA. PAX genes: roles in development, pathophysiology, and cancer. Biochem Pharmacol. 2006;73(1):1–14.

    PubMed  Google Scholar 

  368. Neubuser A, Koseki H, Balling R. Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev Biol. 1995;170(2):701–16.

    PubMed  CAS  Google Scholar 

  369. Wallin J, Eibel H, Neubuser A, Wilting J, Koseki H, Balling R. Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development. 1996;122(1):23–30.

    PubMed  CAS  Google Scholar 

  370. Hetzer-Egger C, Schorpp M, Haas-Assenbaum A, Balling R, Peters H, Boehm T. Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur J Immunol. 2002;32(4):1175–81.

    PubMed  CAS  Google Scholar 

  371. Peters H, Neubuser A, Kratochwil K, Balling R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 1998;12(17):2735–47.

    PubMed  CAS  Google Scholar 

  372. Su D, Ellis S, Napier A, Lee K, Manley NR. Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev Biol. 2001;236(2):316–29.

    PubMed  CAS  Google Scholar 

  373. Su DM, Manley NR. Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development. J Immunol. 2000;164(11):5753–60.

    PubMed  CAS  Google Scholar 

  374. Machado AF, Martin LJ, Collins MD. Pax3 and the splotch mutations: structure, function, and relationship to teratogenesis, including gene-chemical interactions. Curr Pharm Des. 2001;7(9): 751–85.

    PubMed  CAS  Google Scholar 

  375. Conway SJ, Bundy J, Chen J, Dickman E, Rogers R, Will BM. Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc Res. 2000;47(2):314–28.

    PubMed  CAS  Google Scholar 

  376. Epstein JA, Li J, Lang D, et al. Migration of cardiac neural crest cells in Splotch embryos. Development. 2000;127(9):1869–78.

    PubMed  CAS  Google Scholar 

  377. Jemc J, Rebay I. The eyes absent family of phosphotyrosine phosphatases: properties and roles in developmental regulation of transcription. Annu Rev Biochem. 2007;76:513–38.

    PubMed  CAS  Google Scholar 

  378. Kalatzis V, Sahly I, El-Amraoui A, Petit C. Eya1 expression in the developing ear and kidney: towards the understanding of the pathogenesis of Branchio-Oto-Renal (BOR) syndrome. Dev Dyn. 1998;213(4):486–99.

    PubMed  CAS  Google Scholar 

  379. Xu PX, Zheng W, Laclef C, et al. Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development. 2002;129(13):3033–44.

    PubMed  CAS  Google Scholar 

  380. Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426(6964):247–54.

    PubMed  CAS  Google Scholar 

  381. Laclef C, Souil E, Demignon J, Maire P. Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice. Mech Dev. 2003;120(6):669–79.

    PubMed  CAS  Google Scholar 

  382. Zou D, Silvius D, Davenport J, Grifone R, Maire P, Xu PX. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev Biol. 2006;293(2):499–512.

    PubMed  CAS  Google Scholar 

  383. Ozaki H, Watanabe Y, Takahashi K, et al. Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Mol Cell Biol. 2001;21(10):3343–50.

    PubMed  CAS  Google Scholar 

  384. Lindsay EA. Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet. 2001;2(11):858–68.

    PubMed  CAS  Google Scholar 

  385. Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27(3): 286–91.

    PubMed  CAS  Google Scholar 

  386. Bachiller D, Klingensmith J, Shneyder N, et al. The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development. 2003;130(15): 3567–78.

    PubMed  CAS  Google Scholar 

  387. Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410(6824):97–101.

    PubMed  CAS  Google Scholar 

  388. Chapman DL, Garvey N, Hancock S, et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev Dyn. 1996;206(4):379–90.

    PubMed  CAS  Google Scholar 

  389. Xu H, Cerrato F, Baldini A. 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. 2005;132(19):4387–95.

    PubMed  CAS  Google Scholar 

  390. Vitelli F, Taddei I, Morishima M, Meyers EN, Lindsay EA, Baldini A. A genetic link between Tbx1 and fibroblast growth factor signaling. Development. 2002;129(19):4605–11.

    PubMed  CAS  Google Scholar 

  391. Xu H, Morishima M, Wylie JN, et al. Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development. 2004;131(13):3217–27.

    PubMed  CAS  Google Scholar 

  392. Ivins S, Lammerts van Beuren K, Roberts C, et al. Microarray analysis detects differentially expressed genes in the pharyngeal region of mice lacking Tbx1. Dev Biol. 2005;285(2): 554–69.

    PubMed  CAS  Google Scholar 

  393. Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature. 1993;364(6436):412–20.

    PubMed  CAS  Google Scholar 

  394. Cunliffe VT, Furley AJ, Keenan D. Complete rescue of the nude mutant phenotype by a wild-type Foxn1 transgene. Mamm Genome. 2002;13(5):245–52.

    PubMed  CAS  Google Scholar 

  395. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994;372(6501):103–7.

    PubMed  CAS  Google Scholar 

  396. Reth M. Immunodeficiency. Trapping the nude mouse gene. Curr Biol. 1995;5(1):18–20.

    PubMed  CAS  Google Scholar 

  397. Pignata C, Gaetaniello L, Masci AM, et al. Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation. Blood. 2001;97(4):880–5.

    PubMed  CAS  Google Scholar 

  398. Adriani M, Martinez-Mir A, Fusco F, et al. Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann Hum Genet. 2004;68(Pt 3):265–8.

    PubMed  CAS  Google Scholar 

  399. Auricchio L, Adriani M, Frank J, Busiello R, Christiano A, Pignata C. Nail dystrophy associated with a heterozygous mutation of the nude/SCID human FOXN1 (WHN) gene. Arch Dermatol. 2005;141(5):647–8.

    PubMed  Google Scholar 

  400. Lee D, Prowse DM, Brissette JL. Association between mouse nude gene expression and the initiation of epithelial terminal differentiation. Dev Biol. 1999;208(2):362–74.

    PubMed  CAS  Google Scholar 

  401. Ye H, Kelly TF, Samadani U, et al. Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues. Mol Cell Biol. 1997;17(3):1626–41.

    PubMed  CAS  Google Scholar 

  402. Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006;441(7096):992–6.

    PubMed  CAS  Google Scholar 

  403. Itoi M, Tsukamoto N, Amagai T. Expression of Dll4 and CCL25 in Foxn1-negative epithelial cells in the post-natal thymus. Int Immunol. 2007;19(2):127–32.

    PubMed  CAS  Google Scholar 

  404. Boehm T, Bleul CC. Thymus-homing precursors and the thymic microenvironment. Trends Immunol. 2006;27(10):477–84.

    PubMed  CAS  Google Scholar 

  405. Su DM, Navarre S, Oh WJ, Condie BG, Manley NR. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol. 2003;4(11):1128–35.

    PubMed  CAS  Google Scholar 

  406. Tsukamoto N, Itoi M, Nishikawa M, Amagai T. Lack of Delta like 1 and 4 expressions in nude thymus anlages. Cell Immunol. 2005;234(2):77–80.

    PubMed  CAS  Google Scholar 

  407. Bleul CC, Boehm T. Laser capture microdissection-based expression profiling identifies PD1-ligand as a target of the nude locus gene product. Eur J Immunol. 2001;31(8):2497–503.

    PubMed  CAS  Google Scholar 

  408. Liu C, Saito F, Liu Z, et al. Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood. 2006;108(8):2531–9.

    PubMed  CAS  Google Scholar 

  409. Tsai PT, Lee RA, Wu H. BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood. 2003;102(12):3947–53.

    PubMed  CAS  Google Scholar 

  410. Gunther T, Chen ZF, Kim J, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature. 2000;406(6792):199–203.

    PubMed  CAS  Google Scholar 

  411. Liu Z, Yu S, Manley NR. Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol. 2007;305(1):333–46.

    PubMed  CAS  Google Scholar 

  412. Yang A, Schweitzer R, Sun D, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398(6729):714–8.

    PubMed  CAS  Google Scholar 

  413. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708–13.

    PubMed  CAS  Google Scholar 

  414. Blanpain C, Fuchs E. p63: revving up epithelial stem-cell potential. Nat Cell Biol. 2007;9(7):731–3.

    PubMed  CAS  Google Scholar 

  415. McKeon F. p63 and the epithelial stem cell: more than status quo? Genes Dev. 2004;18(5):465–9.

    PubMed  CAS  Google Scholar 

  416. Candi E, Rufini A, Terrinoni A, et al. {Delta}Np63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci U S A. 2007;104(29):11999–2004.

    PubMed  CAS  Google Scholar 

  417. Balciunaite G, Keller MP, Balciunaite E, et al. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol. 2002;3(11):1102–8.

    PubMed  CAS  Google Scholar 

  418. Osada M, Ito E, Fermin HA, et al. The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clin Dev Immunol. 2006;13(2–4):299–319.

    PubMed  CAS  Google Scholar 

  419. Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A. 1998;95(20):11822–7.

    PubMed  CAS  Google Scholar 

  420. Kuraguchi M, Wang XP, Bronson RT, et al. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genet. 2006;2(9):e146.

    PubMed  Google Scholar 

  421. Bleul CC, Boehm T. BMP signaling is required for normal thymus development. J Immunol. 2005;175(8):5213–21.

    PubMed  CAS  Google Scholar 

  422. Patel SR, Gordon J, Mahbub F, Blackburn CC, Manley NR. Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expr Patterns. 2006;6(8):794–9.

    PubMed  CAS  Google Scholar 

  423. Ma L, Liu J, Wu T, et al. ‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation. Development. 2003;130(2):379–89.

    PubMed  CAS  Google Scholar 

  424. Outram SV, Varas A, Pepicelli CV, Crompton T. Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte. Immunity. 2000;13(2):187–97.

    PubMed  CAS  Google Scholar 

  425. Sacedon R, Varas A, Hernandez-Lopez C, et al. Expression of hedgehog proteins in the human thymus. J Histochem Cytochem. 2003;51(11):1557–66.

    PubMed  CAS  Google Scholar 

  426. Moore-Scott BA, Manley NR. Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs. Dev Biol. 2005;278(2):323–35.

    PubMed  CAS  Google Scholar 

  427. Garg V, Yamagishi C, Hu T, Kathiriya IS, Yamagishi H, Srivastava D. Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev Biol. 2001;235(1):62–73.

    PubMed  CAS  Google Scholar 

  428. Mulder GB, Manley N, Maggio-Price L. Retinoic acid-induced thymic abnormalities in the mouse are associated with altered pharyngeal morphology, thymocyte maturation defects, and altered expression of Hoxa3 and Pax1. Teratology. 1998;58(6):263–75.

    PubMed  CAS  Google Scholar 

  429. Wendling O, Dennefeld C, Chambon P, Mark M. Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development. 2000;127(8):1553–62.

    PubMed  CAS  Google Scholar 

  430. Daftary GS, Taylor HS. Endocrine regulation of HOX genes. Endocr Rev. 2006;27(4):331–55.

    PubMed  CAS  Google Scholar 

  431. Dupe V, Ghyselinck NB, Wendling O, Chambon P, Mark M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development. 1999;126(22):5051–9.

    PubMed  CAS  Google Scholar 

  432. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313(14):837–41.

    PubMed  CAS  Google Scholar 

  433. Mulder GB, Manley N, Grant J, et al. Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology. 2000;62(4):214–26.

    PubMed  CAS  Google Scholar 

  434. Niederreither K, Vermot J, Le Roux I, Schuhbaur B, Chambon P, Dolle P. The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development. 2003;130(11):2525–34.

    PubMed  CAS  Google Scholar 

  435. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Ann Rev Neurosci. 2006;29:507–38.

    PubMed  CAS  Google Scholar 

  436. Ehrhard PB, Erb P, Graumann U, Otten U. Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-cell clones. Proc Natl Acad Sci U S A. 1993;90(23):10984–8.

    PubMed  CAS  Google Scholar 

  437. Hannestad J, Garcia-Suarez O, Huerta JJ, Esteban I, Naves FJ, Vega JA. TrkA neutrophin receptor protein in the rat and human thymus. Anat Rec. 1997;249(3):373–9.

    PubMed  CAS  Google Scholar 

  438. Aloe L, Micera A, Bracci-Laudiero L, Vigneti E, Turrini P. Presence of nerve growth factor in the thymus of prenatal, postnatal and pregnant rats. Thymus. 1997;24(4):221–31.

    PubMed  CAS  Google Scholar 

  439. Labouyrie E, Parrens M, de Mascarel A, Bloch B, Merlio JP. Distribution of NGF receptors in normal and pathologic human lymphoid tissues. J Neuroimmunol. 1997;77(2):161–73.

    PubMed  Google Scholar 

  440. Parrens M, Labouyrie E, Groppi A, et al. Expression of NGF receptors in normal and pathological human thymus. J Neuroimmunol. 1998;85(1):11–21.

    PubMed  CAS  Google Scholar 

  441. Garcia-Suarez O, Germana A, Hannestad J, et al. TrkA is necessary for the normal development of the murine thymus. J Neuroimmunol. 2000;108(1–2):11–21.

    PubMed  CAS  Google Scholar 

  442. Vacca A, Di Marcotullio L, Giannini G, et al. Thrombospondin-1 is a mediator of the neurotypic differentiation induced by EGF in thymic epithelial cells. Exp Cell Res. 1999;248(1):79–86.

    PubMed  CAS  Google Scholar 

  443. Perez-Pinera P, Garcia-Suarez O, Prieto JG, et al. Thymocyte depletion affects neurotrophin receptor expression in thymic stromal cells. J Anat. 2006;208(2):231–8.

    PubMed  CAS  Google Scholar 

  444. Tacconelli A, Farina AR, Cappabianca L, et al. TrkAIII expression in the thymus. J Neuroimmunol. 2007;183(1–2):151–61.

    PubMed  CAS  Google Scholar 

  445. Taub DD, Longo DL. Insights into thymic aging and regeneration. Immunol Rev. 2005;205:72–93.

    PubMed  CAS  Google Scholar 

  446. Meilin A, Shoham J, Schreiber L, Sharabi Y. The role of thymocytes in regulating thymic epithelial cell growth and function. Scand J Immunol. 1995;42(2):185–90.

    PubMed  CAS  Google Scholar 

  447. Galy AH, Hadden EM, Touraine JL, Hadden JW. Effects of cytokines on human thymic epithelial cells in culture: IL1 induces thymic epithelial cell proliferation and change in morphology. Cell Immunol. 1989;124(1):13–27.

    PubMed  CAS  Google Scholar 

  448. Galy AH, Dinarello CA, Kupper TS, Kameda A, Hadden JW. Effects of cytokines on human thymic epithelial cells in culture. II. Recombinant IL 1 stimulates thymic epithelial cells to produce IL6 and GM-CSF. Cell Immunol. 1990;129(1):161–75.

    PubMed  CAS  Google Scholar 

  449. Galy AH, Spits H. IL-1, IL-4, and IFN-gamma differentially regulate cytokine production and cell surface molecule expression in cultured human thymic epithelial cells. J Immunol. 1991;147(11):3823–30.

    PubMed  CAS  Google Scholar 

  450. Shu S, Naylor P, Touraine JL, Hadden JW. IL-1, ICAM-1, LFA-3, and hydrocortisone differentially regulate cytokine secretion by human fetal thymic epithelial cells. Thymus. 1996;24(2):89–99.

    PubMed  CAS  Google Scholar 

  451. Lagrota-Candido JM, Villa-Verde DM, Vanderlei FH, Jr., Savino W. Extracellular matrix components of the mouse thymus microenvironment. V. Interferon-gamma modulates thymic epithelial cell/thymocyte interactions via extracellular matrix ligands and receptors. Cell Immunol. 1996;170(2):235–44.

    PubMed  Google Scholar 

  452. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211(2):144–56.

    PubMed  CAS  Google Scholar 

  453. Zediak VP, Bhandoola A. Aging and T cell development: interplay between progenitors and their environment. Semin Immunol. 2005;17(5):337–46.

    PubMed  CAS  Google Scholar 

  454. Sutherland JS, Goldberg GL, Hammett MV, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol. 2005;175(4):2741–53.

    PubMed  CAS  Google Scholar 

  455. Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol. 2005;175(5):2982–93.

    PubMed  CAS  Google Scholar 

  456. Goldberg GL, Alpdogan O, Muriglan SJ, et al. Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol. 2007;178(11):7473–84.

    PubMed  CAS  Google Scholar 

  457. Goldberg GL, Sutherland JS, Hammet MV, et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation. 2005;80(11):1604–13.

    PubMed  Google Scholar 

  458. Napolitano LA, Lo JC, Gotway MB, et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS. 2002;16(8):1103–11.

    PubMed  CAS  Google Scholar 

  459. Alpdogan O, Hubbard VM, Smith OM, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood. 2006;107(6):2453–60.

    PubMed  CAS  Google Scholar 

  460. Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood. 2007;109(6):2529–37.

    PubMed  CAS  Google Scholar 

  461. Rossi S, Blazar BR, Farrell CL, et al. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood. 2002;100(2):682–91.

    PubMed  CAS  Google Scholar 

  462. Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. Identification and characterization of thymic epithelial progenitor cells. Immunity. 2002;16(6):803–14.

    PubMed  CAS  Google Scholar 

  463. Chidgey AP, Boyd RL. Stemming the tide of thymic aging. Nat Immunol. 2006;7(10):1013–6.

    PubMed  CAS  Google Scholar 

  464. Chidgey A, Dudakov J, Seach N, Boyd R. Impact of niche aging on thymic regeneration and immune reconstitution. Semin Immunol. 2007;19(5):331–40.

    PubMed  CAS  Google Scholar 

  465. Dondi D, Festuccia C, Piccolella M, Bologna M, Motta M. GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. Oncol Rep. 2006;15(2):393–400.

    PubMed  CAS  Google Scholar 

  466. Pritchard K. Endocrinology and hormone therapy in breast cancer: endocrine therapy in premenopausal women. Breast Cancer Res. 2005;7(2):70–6.

    PubMed  CAS  Google Scholar 

  467. Wang J, Zhou F, Dong M, Wu R, Qian Y. Prolonged gonadotropin-releasing hormone agonist therapy reduced expression of nitric oxide synthase in the endometrium of women with endometriosis and infertility. Fertil Steril. 2006;85(4):1037–44.

    PubMed  CAS  Google Scholar 

  468. Vottero A, Pedori S, Verna M, et al. Final height in girls with central idiopathic precocious puberty treated with gonadotropin-releasing hormone analog and oxandrolone. J Clin Endocrinol Metab. 2006;91(4):1284–7.

    PubMed  CAS  Google Scholar 

  469. Sutherland JS, Spyroglou LS, Muirhead JL, et al. Enhance immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin Cancer Res. 2008;14(4): 1138–49.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Monash Immunology and Stem Cell Laboratories (MISCL), Level 3, Building 75, Monash University, Wellington Road, 3800, Clayton, Victoria, Australia

    Chew-Li Soh, Joanna M.C. Lim, Richard L. Boyd & Ann P. Chidgey

Authors
  1. Chew-Li Soh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna M.C. Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard L. Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ann P. Chidgey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chew-Li Soh .

Editor information

Editors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Vinagolu K. Rajasekhar MSc, MPhil, PhD

  2. Invitrogen Corporation, Frederick, MD, USA

    Mohan C. Vemuri Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Soh, CL., Lim, J.M., Boyd, R.L., Chidgey, A.P. (2009). Epithelial Stem Cells and the Development of the Thymus, Parathyroid, and Skin. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_33

Download citation

Publish with us

Policies and ethics

Search

Navigation