Conditional telomerase induction causes proliferation of hair follicle stem cells

Abstract

TERT, the protein component of telomerase1,2, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells3, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.

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Figure 1: Conditional activation of TERT promotes the anagen phase of the hair follicle cycle.
Figure 2: TERT induction triggers a rapid transition from telogen to anagen.
Figure 3: TERT activates stem cells, depleting BrdU label from LRCs.
Figure 4: TERT's activity in facilitating a transition from telogen to anagen is independent of its function in telomere synthesis.

References

  1. 1

    Blackburn, E. H. Switching and signalling at the telomere. Cell 106, 661–673 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Smogorzewska, A. & De Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004)

    CAS  Article  Google Scholar 

  3. 3

    Morrison, S. J., Prowse, K. R., Ho, P. & Weissman, I. L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996)

    CAS  Article  Google Scholar 

  4. 4

    Yui, J., Chiu, C. P. & Lansdorp, P. M. Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 91, 3255–3262 (1998)

    CAS  Google Scholar 

  5. 5

    Forsyth, N. R., Wright, W. E. & Shay, J. W. Telomerase and differentiation in multicellular organisms: turn it off, turn it on, and turn it off again. Differentiation 69, 188–197 (2002)

    CAS  Article  Google Scholar 

  6. 6

    Blasco, M. A. et al. Telomere shortening and tumour formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997)

    CAS  Article  Google Scholar 

  7. 7

    Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999)

    CAS  Article  Google Scholar 

  9. 9

    Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Stewart, S. A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl Acad. Sci. USA 99, 12606–12611 (2002)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Chang, S., Khoo, C. M., Naylor, M. L., Maser, R. S. & DePinho, R. A. Telomere-based crisis: functional differences between telomerase activation and ALT in tumour progression. Genes Dev. 17, 88–100 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Blasco, M. A. & Hahn, W. C. Evolving views of telomerase and cancer. Trends Cell Biol. 13, 289–294 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Alonso, L. & Fuchs, E. Stem cells in the skin: waste not, Wnt not. Genes Dev. 17, 1189–1200 (2003)

    CAS  Article  Google Scholar 

  15. 15

    Cotsarelis, G., Sun, T. T. & Lavker, R. M. 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 (1990)

    CAS  Article  Google Scholar 

  16. 16

    Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000)

    CAS  Article  Google Scholar 

  17. 17

    Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003)

    CAS  Article  Google Scholar 

  18. 18

    Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Muller-Rover, S. et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol. 117, 3–15 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Ramirez, R. D., Wright, W. E., Shay, J. W. & Taylor, R. S. Telomerase activity concentrates in the mitotically active segments of human hair follicles. J. Invest. Dermatol. 108, 113–117 (1997)

    CAS  Article  Google Scholar 

  22. 22

    Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Wright, D. E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

    CAS  Article  Google Scholar 

  25. 25

    Sawamura, D. et al. Promoter/enhancer cassettes for keratinocyte gene therapy. J. Invest. Dermatol. 112, 828–830 (1999)

    CAS  Article  Google Scholar 

  26. 26

    Hebert, J. M., Rosenquist, T., Gotz, J. & Martin, G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017–1025 (1994)

    CAS  Article  Google Scholar 

  27. 27

    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 95, 605–614 (1998)

    CAS  Article  Google Scholar 

  28. 28

    Trempus, C. S. et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol. 120, 501–511 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

    Sato, N., Leopold, P. L. & Crystal, R. G. Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. J. Clin. Invest. 104, 855–864 (1999)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge technical assistance from the Stanford Transgenic Core Facility and from P. Chu in the Stanford Comparative Medicine Histology Research Core Laboratory. We wish to thank R. DePinho for the use of TERC-/- mice, A. Glick for the use of K5-tTA mice, T. Sun for the gift of AE13 and AE15 antibodies, and K. Braun and V. Horsley for technical insights. We appreciate comments and insights from T. de Lange, R. Nusse, I. Weissman, L. Attardi, J. Sage, A. Brunet, M. Cleary, D. Felsher, P. Khavari and members of the Artandi laboratory. K.Y.S. is supported by a Medical Scientist Training Program Grant. R.I.T. is supported by a Stanford Graduate Fellowship and a NSF Fellowship. A.E.O. is supported by NIAMS. This work was supported by grants from the Rita Allen Foundation, the V Foundation, the NIH and the Stanford Cancer Council to S.E.A.

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Correspondence to Steven E. Artandi.

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Supplementary information

Supplementary Notes

Contains Supplementary Discussion, Supplementary Methods, Supplementary Figure and Supplementary Tables Legends and additional references.

Supplementary Figure S1

Telomeres remain stable and capped in i-TERT mice.

Supplementary Figure S2

Intact differentiation and development in TERT-induced hair follicles.

Supplementary Figure S3

Intact differentiation of the epidermis in i-TERT(+doxy) skin.

Supplementary Figure S4

TERT does not cause a significant change in EGF and EGFR family gene expression as assessed by quantitative real time PCR in mouse embryonic fibroblasts, skin, and primary keratinocytes.

Supplementary Figure S5

TERT does not lead to activation of ERK, a downstream target of the EGFR pathway.

Supplementary Figure S6

TERT induces anagen in hair follicles in mouse tail epithelium.

Supplementary Tables S1-S3

Supplementary Table S1: number of mice biopsied in anagen or telogen at day 50 in each genotype. Supplementary Table S2: three mice were administered doxycycline at day 40, when hair follicles were in telogen. Supplementary Table S3: number of mice that were analyzed in TERC-/-, TERC+/-, or TERC+/+ backgrounds.

Supplementary Table S4

Primer sequences used for SYBR green real-time RT-PCR experiments.

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Sarin, K., Cheung, P., Gilison, D. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005). https://doi.org/10.1038/nature03836

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