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TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.

Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE - PLoS Genet. (2007)

Bottom Line: This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood.We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis.These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford School of Medicine, Stanford, California, United States of America.

ABSTRACT
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

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TERTci Promotes Hair Growth and Activates Hair Follicle Stem Cells(A–B) Mice were shaved at approximately day 50 and hair growth was assessed after 2 wk. Note pink skin in shaved areas of controls, consistent with a continued telogen phase even after 14 d.(C) Dorsal skin biopsies were taken after long-term BrdU chase, and BrdU label retention in the CD34+ bulge stem cell compartment was assessed for non-Tg mice (middle) and iK5-TERTci mice (bottom). A non-Tg mouse that did not receive BrdU serves as a negative control (top). Green, CD34; red, BrdU; 400×.(D) Quantification of the number of BrdU positive cells per CD34+ cell in the bulge region. Conditional expression of TERTci depleted BrdU label from label retaining cells in the hair follicle bulge region. A total of 1,075 CD34+ cells from 75 bulges of four non-Tg mice, and 724 CD34+ cells from 65 bulges of six iK5-TERTci mice were analyzed. Error bars represent standard error.
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pgen-0040010-g002: TERTci Promotes Hair Growth and Activates Hair Follicle Stem Cells(A–B) Mice were shaved at approximately day 50 and hair growth was assessed after 2 wk. Note pink skin in shaved areas of controls, consistent with a continued telogen phase even after 14 d.(C) Dorsal skin biopsies were taken after long-term BrdU chase, and BrdU label retention in the CD34+ bulge stem cell compartment was assessed for non-Tg mice (middle) and iK5-TERTci mice (bottom). A non-Tg mouse that did not receive BrdU serves as a negative control (top). Green, CD34; red, BrdU; 400×.(D) Quantification of the number of BrdU positive cells per CD34+ cell in the bulge region. Conditional expression of TERTci depleted BrdU label from label retaining cells in the hair follicle bulge region. A total of 1,075 CD34+ cells from 75 bulges of four non-Tg mice, and 724 CD34+ cells from 65 bulges of six iK5-TERTci mice were analyzed. Error bars represent standard error.

Mentions: To determine if expression of wild-type TERT or TERTci in the K5 layer caused hair growth, doxycycline-drinking water was withdrawn from double transgenic mice at day 21 to allow TERT upregulation. Mice were then shaved in the second post-natal telogen at day 50 and followed for two weeks. The majority of control mice, including single transgenic mice and non-transgenic mice, showed no hair growth during this period (9/12 mice without hair growth). In marked contrast, nearly all iK5-TERT mice and iK5-TERTci mice showed efficient hair growth during this interval (6/6 iK5-TERT mice and 9/10 iK5-TERTci grew hair, p < 0.01 for both wild-type and mutant TERT versus controls) (Figure 2A and 2B, and Table S2). These data show that conditional upregulation of TERT in the K5 compartment of the hair follicle stimulates robust hair growth through a mechanism that does not require enzymatic function.


TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.

Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE - PLoS Genet. (2007)

TERTci Promotes Hair Growth and Activates Hair Follicle Stem Cells(A–B) Mice were shaved at approximately day 50 and hair growth was assessed after 2 wk. Note pink skin in shaved areas of controls, consistent with a continued telogen phase even after 14 d.(C) Dorsal skin biopsies were taken after long-term BrdU chase, and BrdU label retention in the CD34+ bulge stem cell compartment was assessed for non-Tg mice (middle) and iK5-TERTci mice (bottom). A non-Tg mouse that did not receive BrdU serves as a negative control (top). Green, CD34; red, BrdU; 400×.(D) Quantification of the number of BrdU positive cells per CD34+ cell in the bulge region. Conditional expression of TERTci depleted BrdU label from label retaining cells in the hair follicle bulge region. A total of 1,075 CD34+ cells from 75 bulges of four non-Tg mice, and 724 CD34+ cells from 65 bulges of six iK5-TERTci mice were analyzed. Error bars represent standard error.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211538&req=5

pgen-0040010-g002: TERTci Promotes Hair Growth and Activates Hair Follicle Stem Cells(A–B) Mice were shaved at approximately day 50 and hair growth was assessed after 2 wk. Note pink skin in shaved areas of controls, consistent with a continued telogen phase even after 14 d.(C) Dorsal skin biopsies were taken after long-term BrdU chase, and BrdU label retention in the CD34+ bulge stem cell compartment was assessed for non-Tg mice (middle) and iK5-TERTci mice (bottom). A non-Tg mouse that did not receive BrdU serves as a negative control (top). Green, CD34; red, BrdU; 400×.(D) Quantification of the number of BrdU positive cells per CD34+ cell in the bulge region. Conditional expression of TERTci depleted BrdU label from label retaining cells in the hair follicle bulge region. A total of 1,075 CD34+ cells from 75 bulges of four non-Tg mice, and 724 CD34+ cells from 65 bulges of six iK5-TERTci mice were analyzed. Error bars represent standard error.
Mentions: To determine if expression of wild-type TERT or TERTci in the K5 layer caused hair growth, doxycycline-drinking water was withdrawn from double transgenic mice at day 21 to allow TERT upregulation. Mice were then shaved in the second post-natal telogen at day 50 and followed for two weeks. The majority of control mice, including single transgenic mice and non-transgenic mice, showed no hair growth during this period (9/12 mice without hair growth). In marked contrast, nearly all iK5-TERT mice and iK5-TERTci mice showed efficient hair growth during this interval (6/6 iK5-TERT mice and 9/10 iK5-TERTci grew hair, p < 0.01 for both wild-type and mutant TERT versus controls) (Figure 2A and 2B, and Table S2). These data show that conditional upregulation of TERT in the K5 compartment of the hair follicle stimulates robust hair growth through a mechanism that does not require enzymatic function.

Bottom Line: This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood.We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis.These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford School of Medicine, Stanford, California, United States of America.

ABSTRACT
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

Show MeSH
Related in: MedlinePlus