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Conditional telomerase induction causes proliferation of hair follicle stem cells

Nature volume 436, pages 1048–1052 (2005)Cite this article

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.

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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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Authors and Affiliations

  1. Department of Medicine, Division of Hematology,

    Kavita Y. Sarin, Peggie Cheung, Daniel Gilison, Eunice Lee, Ruth I. Tennen, Estee Wang, Maja K. Artandi & Steven E. Artandi

  2. Cancer Biology Program,

    Ruth I. Tennen, Anthony E. Oro & Steven E. Artandi

  3. Department of Genetics,

    Kavita Y. Sarin & Daniel Gilison

  4. Department of Dermatology, Stanford School of Medicine, Stanford, California, 94305, USA

    Anthony E. Oro

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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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