Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells

Oncogene volume 26, pages 5078–5085 (2007)Cite this article

Abstract

Epithelial stem cells in the bulge region within the hair follicle maintain the cyclic hair growth, but whether these stem cells also contribute to the epidermal renewal remains unclear. Here, we observed that the conditional deletion of the Rac1 gene in the mouse skin, including the potential follicular and epidermal stem cell compartments, results in alopecia owing to defective hair development. Surprisingly, mice lacking the expression of this Rho GTPase do not display major alterations in the interfollicular skin. Furthermore, Rac1 excision from primary epithelial keratinocytes results in the inability to reconstitute hair follicles and sebaceous glands when grafted onto mice, but epithelial cells lacking Rac1 can nonetheless form a healthy epidermis. Together, these findings support the emerging view that the epidermis and the hair follicles are maintained by different epithelial stem cells, and provide evidence that the requirement for Rac1 function can distinguish these distinct stem cells populations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Andl T, Ahn K, Kairo A, Chu EY, Wine-Lee L, Reddy ST et al. (2004). Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development. Development 131: 2257–2268.

    Article  CAS  Google Scholar 

  • Benitah SA, Frye M, Glogauer M, Watt FM . (2005). Stem cell depletion through epidermal deletion of Rac1. Science 309: 933–935.

    Article  Google Scholar 

  • Bickenbach JR . (1981). Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res 60: 1611–1620.

    Article  Google Scholar 

  • Bickenbach JR, McCutecheon J, Mackenzie IC . (1986). Rate of loss of tritiated thymidine label in basal cells in mouse epithelial tissues. Cell Tissue Kinet 19: 325–333.

    CAS  PubMed  Google Scholar 

  • Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E . (2004). Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118: 635–648.

    Article  CAS  Google Scholar 

  • Braun KM, Niemann C, Jensen UB, Sundberg JP, Silva-Vargas V, Watt FM . (2003). Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130: 5241–5255.

    Article  CAS  Google Scholar 

  • Chrostek A, Wu X, Quondamatteo F, Hu R, Sanecka A, Niemann C et al. (2006). Rac1 is crucial for hair follicle integrity but is not essential for maintenance of the epidermis. Mol Cell Biol 26: 6957–6970.

    Article  CAS  PubMed Central  Google Scholar 

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N et al. (1995). The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81: 1137–1146.

    Article  CAS  Google Scholar 

  • Cotsarelis G . (2006). Epithelial stem cells: a folliculocentric view. J Invest Dermatol 126: 1459–1468.

    Article  CAS  Google Scholar 

  • Cotsarelis G, Millar SE . (2001). Towards a molecular understanding of hair loss and its treatment. Trends Mol Med 7: 293–301.

    Article  CAS  Google Scholar 

  • Cotsarelis G, Sun TT, Lavker RM . (1990). Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61: 1329–1337.

    Article  CAS  Google Scholar 

  • Etienne-Manneville S, Hall A . (2002). Rho GTPases in cell biology. Nature 420: 629–635.

    Article  CAS  Google Scholar 

  • Fuchs E, Raghavan S . (2002). Getting under the skin of epidermal morphogenesis. Nat Rev Genet 3: 199–209.

    Article  CAS  Google Scholar 

  • Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC et al. (2003). Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302: 445–449.

    Article  CAS  Google Scholar 

  • Gutkind JS, Novotny EA, Brann MR, Robbins KC . (1991). Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci USA 88: 4703–4707.

    Article  CAS  Google Scholar 

  • Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ et al. (2005). Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11: 1351–1354.

    Article  CAS  Google Scholar 

  • Levy V, Lindon C, Harfe BD, Morgan BA . (2005). Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell 9: 855–861.

    Article  CAS  Google Scholar 

  • Lichti U, Weinberg WC, Goodman L, Ledbetter S, Dooley T, Morgan D et al. (1993). In vivo regulation of murine hair growth: insights from grafting defined cell populations onto nude mice. J Invest Dermatol 101: 124S–129S.

    Article  CAS  Google Scholar 

  • Millar SE . (2002). Molecular mechanisms regulating hair follicle development. J Invest Dermatol 118: 216–225.

    Article  CAS  Google Scholar 

  • Morris RJ, Fischer SM, Slaga TJ . (1985). Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J Invest Dermatol 84: 277–281.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Squarize CH, Castilho RM, Santos Pinto Jr D . (2002). Immunohistochemical evidence of PTEN in oral squamous cell carcinoma and its correlation with the histological malignancy grading system. J Oral Pathol Med 31: 379–384.

    Article  CAS  Google Scholar 

  • Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M et al. (1998). Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer 77: 147–152.

    Article  CAS  PubMed Central  Google Scholar 

  • Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM . (2000). Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102: 451–461.

    Article  CAS  Google Scholar 

  • Verdier-Sevrain S, Bonte F, Gilchrest B . (2006). Biology of estrogens in skin: implications for skin aging. Exp Dermatol 15: 83–94.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked ‘advertisement’ in accordance with 18 USC Section 1734 solely to indicate this fact.

Author information

Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    R M Castilho, C H Squarize, V Patel, A Molinolo & J S Gutkind

  2. Departments of Dermatology and Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    S E Millar

  3. Division of Experimental Hematology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

    Y Zheng

Authors
  1. R M Castilho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C H Squarize
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S E Millar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Molinolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J S Gutkind
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J S Gutkind.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castilho, R., Squarize, C., Patel, V. et al. Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells. Oncogene 26, 5078–5085 (2007). https://doi.org/10.1038/sj.onc.1210322

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210322

Keywords

This article is cited by

Search

Advanced search

Quick links