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Cited by 425Hair Growth and DisordersTelomeres, Telomerase, and Senescencedental development and anomalies

Conditional telomerase induction causes proliferation of hair follicle stem cells

Open access
Sarin, Kavita Y., Cheung, Peggie, Gilison, Daniel, Lee, Eunice, Tennen, Ruth I., Wang, Estee, Artandi, Maja K., Oro, Anthony E. +1 more·2005·Nature
DOI 10.1038/nature03836PMC PMC1361120
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Abstract

TERT, the protein component of telomerase, 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 cells, 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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Written from the paper’s full text.

TL;DR

Conditional transgenic induction of TERT in mouse skin epithelium is sufficient to drive the telogen-to-anagen transition of the hair follicle cycle and promote hair growth by causing proliferation of quiescent bulge stem cells. This activity does not require TERC and therefore operates independently of telomere synthesis.

Key findings

  • Doxycycline-induced TERT expression in i-TERT mice kept hair follicles in anagen at day 50, whereas i-TERT mice off doxycycline and non-transgenic mice had exited to telogen; the effect occurred with 100% penetrance (18/18 in anagen; chi-square p<0.0001 for i-TERT on vs. off doxycycline).
  • Inducing TERT after follicles had entered the prolonged second telogen (day 40) drove anagen entry by day 9 and mid-anagen by day 12 (p=0.005), and doxycycline-treated i-TERT mice shaved at day 55 showed significant hair growth at 14 days versus controls, which showed none.
  • TERT caused proliferation of quiescent bulge stem cells: BrdU label in CD34+ bulge cells was depleted by 76% (BrdU+ cells/CD34+ cell, p<0.0001) after five weeks of doxycycline, while CD34+ cell numbers remained similar, suggesting division with self-renewal.
  • The effect is TERC-independent: conditional TERT activation induced anagen in 5/5 i-TERT;TERC−/− mice (p=0.0003 vs. i-TERT off doxycycline), identical to TERC+/+ and TERC+/− backgrounds (6/6 in anagen), despite confirmed absence of telomerase activity and TERC RNA.
  • Effects were epithelium-intrinsic: K5-tTA+;tetop-TERT+ mice showed anagen in 5/5 versus telogen in 6/6 littermate controls (p=0.0009), and interfollicular epidermal proliferation was unchanged (4.2 Ki-67+ cells/100μm in i-TERT day 50 vs. 4.3 in non-transgenic day 28).

Methods

  • Conditional tetracycline-regulated transgenic system: mouse TERT cDNA under a tetracycline-responsive promoter (tetop-TERT) crossed with actin-rtTA mice to generate inducible TERT (i-TERT) mice, with doxycycline administered in drinking water; a K5-tTA;tetop-TERT cross (tet-off) restricted expression to the basal layer/outer root sheath.
  • Telomerase activity and expression assessed by TRAP assay, Northern blot, RT-PCR, and RNA in situ hybridization; hair cycle stage assessed by H&E histology of dorsal skin biopsies.
  • Bulge stem cells marked by repeated BrdU injections at 10 days of age followed by a long chase (45–90 days) and visualized by BrdU/CD34 double immunofluorescence on sections and tail epidermal wholemounts; TERC+/− mice backcrossed to FVB/N for six generations were intercrossed to yield TERC+/+, +/−, and −/− i-TERT cohorts.

Limitations

  • The paper states that in this transgenic context "either altered timing of TERT expression or higher protein levels may be important in mediating these new activities for TERT," and calls for loss-of-function studies and experiments to determine whether TERT's function in stem cell proliferation is cell autonomous.
  • Evident from the text: the conclusions rest on transgenic TERT overexpression rather than endogenous TERT, so the physiological relevance of the non-canonical activity is not established here.
  • Evident from the text: mechanistic details of the TERC-independent pathway are not identified, and the work is confined to mouse skin/hair follicle biology.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature03836

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    After doxycycline treatment of telogen i-TERT mice, TERT mRNA and telomerase activity progressively increased from day 3 through day 9.

    “TERT mRNA and telomerase activity progressively increased from day 3 through day 9 (Fig 2a).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Within several weeks of doxycycline treatment, the coats of i-TERT mice were significantly altered.

    “Remarkably, within several weeks of doxycycline treatment, the coats of i-TERT mice were significantly altered, reminiscent of mice with known mutations that affect hair follicle cycling26,27 (Fig 1e).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

  • Findingown data
    § Abstract

    Conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen to anagen, thereby facilitating robust hair growth.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    The new function of TERT in promoting the telogen-to-anagen transition does not require the telomerase RNA component (TERC).

    “This new function for TERT does not require the telomerase RNA component (TERC), which encodes the template for telomere addition, and therefore operates through a novel mechanism independent of its activity in synthesizing telomere repeats.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Telomere synthesis requires both TERT and TERC.
  • Findingown data
    § Abstract

    Expression of TERT mRNA in skin epithelium induced anagen in 5/5 K5-tTA+; tetop-TERT+ mice, whereas all littermate control biopsies were in telogen (6/6).

    “Expression of TERT mRNA in skin epithelium (data not shown) induced anagen in 5/5 K5-tTA+; tetop-TERT+ mice, whereas all littermate control biopsies were in telogen (6/6, p=0.0009 by Chi square analysis)(Fig. 3h).”
    Quote in the paperSubstantial claim
  • May combine two claims. 7
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data
    § Abstract

    The effect of TERT induction on maintaining anagen was doxycycline-dependent and occurred with 100% penetrance in i-TERT mice (18/18 in anagen).

    “This effect was doxycycline-dependent and occurred with 100% penetrance in i-TERT mice (18/18 in anagen) (chi square analysis, p<0.0001 for i-TERT on vs. off doxycycline, Table S1).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Abstract

    Hair follicles from i-TERT mice on doxycycline were consistently in anagen at day 50, whereas follicles from i-TERT mice off doxycycline and from non-transgenic mice had exited anagen into the second postnatal telogen phase.

    “In marked contrast, hair follicles from i-TERT mice on doxycycline were consistently in anagen at day 50 (Fig 1f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    In mouse skin, telomerase activity strongly correlates with the first and second anagen phases and is not detected during telogen phases.

    “Telomerase activity strongly correlated with the first and second anagen phases and was not detected during telogen phases (Fig 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Follicles from i-TERT mice treated with doxycycline entered anagen by day 9 and were in mid-anagen by day 12, whereas non-transgenic follicles remained in telogen.

    “Whereas hair follicles from non-transgenic mice remained in telogen during the duration of the time course, follicles from i-TERT mice treated with doxycycline entered anagen by day 9 and were in mid-anagen20 by day 12 (Fig 2b) (chi-square analysis, p=0.005, Table S2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § Abstract

    Northern blot and TRAP assay confirmed doxycycline-dependent induction of the TERT transgene and increased telomerase activity in the skin of i-TERT mice.

    “Northern blot and TRAP assay confirmed doxycycline-dependent induction of the TERT transgene and increased telomerase activity in the skin of i-TERT mice (Fig 1c, d) as well as in other tissues (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    Conditional activation of TERT protein in mouse skin is sufficient to induce proliferation of hair follicle stem cells, and this function is independent of its role in telomere synthesis.

    “Here we show that conditional activation of TERT protein in mouse skin is sufficient to induce proliferation of hair follicle stem cells and that this function is independent of its role in telomere synthesis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Telomere synthesis requires both TERT and TERC.

  • May combine two claims.

    Interpretationown data
    § Abstract

    Induction of TERT in telogen follicles is sufficient to initiate a transition to the anagen phase and promote new hair synthesis.

    “Strikingly, these results show that induction of TERT in telogen follicles is sufficient to initiate a transition to the anagen phase and promote new hair synthesis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    TERT promotes tumor development even in settings of ample telomere reserve.

    “Moreover, recent findings indicate that TERT promotes tumor development even in settings of ample telomere reserve, although the mechanisms underlying these telomere length-independent activities of TERT remain unclear9–13.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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) source

      Not checked in the free run.

    • cites [10] Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Induction of anagen can occur through signals from the dermal papilla.

    “While induction of anagen can occur through signals from the dermal papilla30, the lack of detectable levels of TERT mRNA in the dermal papilla (Fig. 1h) makes it unlikely in this case.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    BrdU label persists in quiescent bulge cells for more than six months.

    “consistent with previous observations that BrdU label persists in quiescent bulge cells for more than six months17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Initiation of a new anagen cycle depends upon activation of a small number of quiescent stem cells that reside in the bulge.

    “Initiation of a new anagen cycle depends upon activation of a small number of quiescent stem cells that reside in the bulge, a niche at the follicle base15–19.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

    • cites [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) source

      Not checked in the free run.

    • cites [18] Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004) source

      Not checked in the free run.

    • cites [19] Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    In normal tissues, TERT is expressed in stem cells and in progenitor cells.

    “In normal tissues, TERT is expressed in stem cells and in progenitor cells3, but its role in these compartments is not fully understood.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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) source

      Not checked in the free run.

12 of 12

  • The paper relies on this without support.

    Telomere synthesis requires both TERT and TERC.

    “Telomere synthesis requires both TERT and TERC; therefore, if the effects of TERT are retained in a TERC−/− background, telomere extension cannot be required for stem cell activation events mediated by TERT.”

  • The paper relies on this without support.

    The role of TERT in stem cell and progenitor cell compartments is not fully understood.

    “In normal tissues, TERT is expressed in stem cells and in progenitor cells3, but its role in these compartments is not fully understood.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tert overexpression improves the ability of epidermal stem cells to regenerate skin and hair.

    “Interestingly, Tert overexpression can also improve the ability of epidermal stem cells to regenerate the skin and the hair 60, 69 .”

    From The common biology of cancer and ageing (2007) · cites this paper as [69]

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Authors
Sarin, K. Y., Cheung, P., Gilison, D., Lee, E., Tennen, R. I., Wang, E., Artandi, M. K., Oro, A. E., & Artandi, S. E.
Affiliations
Stanford Medicine (US)
Corresponding author
Artandi, Steven E.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2005-08
Volume
436
Issue
7053
Pages
1048-1052
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature03836
PMC
PMC1361120
OpenAlex
W2085786821
Semantic Scholar
a1d495197e4ad7bb2a02c41da2b56eb0a48446e4
Cited by
425
References
30
Citations by year
2026: 6 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 9 · 2020: 17 · 2019: 7 · 2018: 14 · 2017: 13 · 2016: 25 · 2015: 14 · 2014: 17 · 2013: 22 · 2012: 33
FWCI
38.35
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Cancer Institute (R55CA109088, K08CA082176)
  • National Institute of General Medical Sciences (T32GM007365)
Topics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
Keywords
telomerase reverse transcriptase, hair follicle stem cells, hair cycle, telogen-to-anagen transition, stem cell proliferation, skin epithelium, telomere maintenance, tissue regeneration, aging
MeSH terms
Animals, Bromodeoxyuridine, DNA-Binding Proteins, Enzyme Induction, Mice, Transgenic, RNA, Stem Cells, Hair Follicle, Transgenes, Telomerase, Cell Proliferation, Mice

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