Elucidation of molecular mechanisms underlying stem cell regulation is of great importance for their clinical applications in regenerative medicine and cancer therapy. The function of stem cells is maintained by their specialized microenvironment, referred as the niche. Despite intensive studies of the stem cell niche, the molecular basis of stem cell regulation by the niche has still remained elusive. Since molecular interactions between stem cells and the niche can be analyzed only under in vivo conditions, one drawback that hampers stem cell research is the lack of an efficient in vivo assay system that allow to define an in vivo gene function for the regulation of stem cells. We have previously identified melanocyte stem cells (MSCs) in the mouse hair follicle, in which MSCs reside at a specific region of the hair follicle, termed as the lower permanent portion. MSCs offer an attractive model with which to study the molecular basis of stem cell regulation, because loss-of-function mutations in the genes responsible for MSC regulation are readily identifiable by a premature hair graying phenotype in mice. This implies the irresistible possibility that MSCs allows us to identify the genes involved in stem cell regulation by a phenotype-driven genetic screen in mice. Hence, we believe that MSC system is an excellent model to study stem cell biology.
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References
Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442: 823–6.
Aoki Y, Saint-Germain N, Gyda M, Magner-Fink E, Lee YH, Credidio C, Saint-Jeannet JP (2003) Sox10 regulates the development of neural crest-derived melanocytes in Xenopus. Dev Biol 259: 19–33.
Arck PC, Overall R, Spatz K, Liezman C, Handjiski B, Klapp BF, Birch-Machin MA, Peters EM (2006) Towards a “free radical theory of graying”: melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. Faseb J 20: 1567–9.
Benfey PN (1999) Stem cells: A tale of two kingdoms. Curr Biol 9: R171–2.
Bennett DC, Lamoreux ML (2003) The color loci of mice–a genetic century. Pigment Cell Res 16: 333–44.
Biswas SC, Shi Y, Sproul A, Greene LA (2007) Pro-apoptotic Bim induction in response to nerve growth factor deprivation requires simultaneous activation of three different death signaling pathways. J Biol Chem 282: 29368–74.
Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 1: 645–53.
Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek KS, Testori A, Larue L, Goding CR (2006) Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev 20: 3426–39.
Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT (2000) Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287: 1804–8.
Conboy IM, Conboy MJ, Smythe GM, Rando TA (2003) Notch-mediated restoration of regenerative potential to aged muscle. Science 302: 1575–7.
Domen J, Cheshier SH, Weissman IL (2000) The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med 191: 253–64.
Fitch DH (2005) Evolution: an ecological context for C. elegans. Curr Biol 15: R655–8.
Goding CR (2000) Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. Genes Dev 14: 1712–28.
Gray JV, Petsko GA, Johnston GC, Ringe D, Singer RA, Werner-Washburne M (2004) “Sleeping beauty”: quiescence in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 68: 187–206.
Gros J, Manceau M, Thome V, Marcelle C (2005) A common somitic origin for embryonic muscle progenitors and satellite cells. Nature 435: 954–8.
Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X, Wu H (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294: 2186–9.
Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408: 255–62.
Guyonneau L, Murisier F, Rossier A, Moulin A, Beermann F (2004) Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice. Mol Cell Biol 24: 3396–403.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12: 446–51.
Jordan SA, Jackson IJ (2000) A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos. Mech Dev 92: 135–43.
Kassar-Duchossoy L, Giacone E, Gayraud-Morel B, Jory A, Gomes D, Tajbakhsh S (2005) Pax3/Pax7 mark a novel population of primitive myogenic cells during development. Genes Dev 19: 1426–31.
Kawamoto S, Niwa H, Tashiro F, Sano S, Kondoh G, Takeda J, Tabayashi K, Miyazaki J (2000) A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett 470: 263–8.
Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT (2001) Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294: 2542–5.
Kippin TE, Martens DJ, van der Kooy D (2005) p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev 19: 756–67.
Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E (2007) 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 104: 10063–8.
Kunisada T, Lu SZ, Yoshida H, Nishikawa S, Nishikawa S, Mizoguchi M, Hayashi S, Tyrrell L, Williams DA, Wang X, Longley BJ (1998) Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J Exp Med 187: 1565–73.
Lang D, Lu MM, Huang L, Engleka KA, Zhang M, Chu EY, Lipner S, Skoultchi A, Millar SE, Epstein JA (2005) Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 433: 884–7.
Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21: 605–31.
Lin JY, Fisher DE (2007) Melanocyte biology and skin pigmentation. Nature 445: 843–50.
Mackenzie MA, Jordan SA, Budd PS, Jackson IJ (1997) Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo. Dev Biol 192: 99–107.
Mak SS, Moriyama M, Nishioka E, Osawa M, Nishikawa S (2006) Indispensable role of Bcl2 in the development of the melanocyte stem cell. Dev Biol 291: 144–53.
Moriyama M, Osawa M, Mak SS, Ohtsuka T, Yamamoto N, Han H, Delmas V, Kageyama R, Beermann F, Larue L, Nishikawa S (2006) Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 173: 333–9.
Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA, Cotsarelis G (2004) Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22: 411–7.
Nishikawa S, Kusakabe M, Yoshinaga K, Ogawa M, Hayashi S, Kunisada T, Era T, Sakakura T, Nishikawa S (1991) In utero manipulation of coat color formation by a monoclonal anti-c-kit antibody: two distinct waves of c-kit-dependency during melanocyte development. Embo J 10: 2111–8.
Nishimura EK, Granter SR, Fisher DE (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307: 720–4.
Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, Jackson IJ, Barrandon Y, Miyachi Y, Nishikawa S (2002) Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416: 854–60.
Osawa M, Egawa G, Mak SS, Moriyama M, Freter R, Yonetani S, Beermann F, Nishikawa S (2005) Molecular characterization of melanocyte stem cells in their niche. Development 132: 5589–99.
Quevedo WC, Jr., Holstein TJ (1992) Molecular genetics and the ontogeny of pigment patterns in mammals. Pigment Cell Res 5: 328–34.
Radonjic M, Andrau JC, Lijnzaad P, Kemmeren P, Kockelkorn TT, van Leenen D, van Berkum NL, Holstege FC (2005) Genome-wide analyses reveal RNA polymerase II located upstream of genes poised for rapid response upon S. cerevisiae stationary phase exit. Mol Cell 18: 171–83.
Reid K, Nishikawa S, Bartlett PF, Murphy M (1995) Steel factor directs melanocyte development in vitro through selective regulation of the number of c-kit + progenitors. Dev Biol 169: 568–79.
Relaix F, Rocancourt D, Mansouri A, Buckingham M (2005) A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435: 948–53.
Rossi DJ, Seita J, Czechowicz A, Bhattacharya D, Bryder D, Weissman IL (2007) Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle 6: 2371–6.
Samokhvalov IM, Samokhvalova NI, Nishikawa S (2007) Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446: 1056–61.
Schouwey K, Delmas V, Larue L, Zimber-Strobl U, Strobl LJ, Radtke F, Beermann F (2007) Notch1 and Notch2 receptors influence progressive hair graying in a dose-dependent manner. Dev Dyn 236: 282–9.
Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ (2005) Hair follicle pigmentation. J Invest Dermatol 124: 13–21.
Spradling A, Drummond-Barbosa D, Kai T (2001) Stem cells find their niche. Nature 414: 98–104.
Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81: 449–94.
Suda T, Arai F, Hirao A (2005) Hematopoietic stem cells and their niche. Trends Immunol 26: 426–33.
Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325–39.
Tulina N, Matunis E (2001) Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 294: 2546–9.
Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E (2004) Defining the epithelial stem cell niche in skin. Science 303: 359–63.
van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8: 440–50.
Walkley CR, Fero ML, Chien WM, Purton LE, McArthur GA (2005) Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 7: 172–8.
Watt FM, Hogan BL (2000) Out of Eden: stem cells and their niches. Science 287: 1427–30.
Wegner M (2005) Secrets to a healthy Sox life: lessons for melanocytes. Pigment Cell Res 18: 74–85.
Yonetani S, Moriyama M, Nishigori C, Osawa M, Nishikawa SI (2007) In Vitro Expansion of Immature Melanoblasts and their Ability to Repopulate Melanocyte Stem Cells in the Hair Follicle. J Invest Dermatol.
Yoshida H, Hayashi S, Shultz LD, Yamamura K, Nishikawa S, Nishikawa S, Kunisada T (1996) Neural and skin cell-specific expression pattern conferred by steel factor regulatory sequence in transgenic mice. Dev Dyn 207: 222–32.
Yoshida S, Sukeno M, Nakagawa T, Ohbo K, Nagamatsu G, Suda T, Nabeshima Y (2006) The first round of mouse spermatogenesis is a distinctive program that lacks the self-renewing spermatogonia stage. Development 133: 1495–505.
Yusuf I, Fruman DA (2003) Regulation of quiescence in lymphocytes. Trends Immunol 24: 380–6.
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Osawa, M., Hasegawa, K., Moriyama, M., Nishikawa, SI. (2008). Melanocyte Stem Cells: As an Excellent Model to Study Stem Cell Biology. In: Bosch, T.C.G. (eds) Stem Cells. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8274-0_8
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