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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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Both TERT and TERTci Enhance Proliferation of Interfollicular Epidermis in Mouse Skin(A) Expression of either TERT or TERTci increases thickness of interfollicular epidermis (IFE; black arrows). Dorsal skins were biopsied at days 55–60 and stained with H&E. Controls include non-transgenic and single-transgenic mice.(B) Quantification shows significant thickening of IFE in both iK5-TERT and iK5-TERTci (12 control, eight iK5-TERT, and 14 iK5-TERTci mice were analyzed. p < 0.00001 by one-way ANOVA and p < 0.05 by Student's t-test between control and iK5-TERT).(C,E) Expression of either TERT or TERTci increases proliferation in the basal layer of IFE. Abundance of Ki-67+ cells is increased in IFE of iK5-TERT and iK5-TERTci mice at days 55–60. Ki-67+ cells are stained by DAB (C) (black arrows), hematoxylin counterstain. Double immunostaining for Keratin 14 and Ki-67 (E). Green, K14; Red, Ki-67.(D,F) Quantification of Ki-67 staining shows significant increase in proliferation index. (D) Number of Ki-67+ cells per 100 μm. (F) Percentage of Ki-67+ cells within the basal layer of IFE (p < 0.0001 by one-way ANOVA and p < 0.01 by Student's t-test between control and iK5-TERT).
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pgen-0040010-g003: Both TERT and TERTci Enhance Proliferation of Interfollicular Epidermis in Mouse Skin(A) Expression of either TERT or TERTci increases thickness of interfollicular epidermis (IFE; black arrows). Dorsal skins were biopsied at days 55–60 and stained with H&E. Controls include non-transgenic and single-transgenic mice.(B) Quantification shows significant thickening of IFE in both iK5-TERT and iK5-TERTci (12 control, eight iK5-TERT, and 14 iK5-TERTci mice were analyzed. p < 0.00001 by one-way ANOVA and p < 0.05 by Student's t-test between control and iK5-TERT).(C,E) Expression of either TERT or TERTci increases proliferation in the basal layer of IFE. Abundance of Ki-67+ cells is increased in IFE of iK5-TERT and iK5-TERTci mice at days 55–60. Ki-67+ cells are stained by DAB (C) (black arrows), hematoxylin counterstain. Double immunostaining for Keratin 14 and Ki-67 (E). Green, K14; Red, Ki-67.(D,F) Quantification of Ki-67 staining shows significant increase in proliferation index. (D) Number of Ki-67+ cells per 100 μm. (F) Percentage of Ki-67+ cells within the basal layer of IFE (p < 0.0001 by one-way ANOVA and p < 0.01 by Student's t-test between control and iK5-TERT).

Mentions: Although the skin, or interfollicular epidermis (IFE), is repaired by progeny of hair follicle bulge stem cells during wounding, renewal of the IFE under homeostatic conditions is maintained by long-lived stem cells or progenitor cells in the basal layer of the IFE [28,29]. To determine if TERT affects progenitor cells in this basal layer, we examined the IFE in detail. The IFE was significantly thickened in both iK5-TERT mice (17.43 μm, p < 0.05) and in iK5-TERTci mice (24.33 μm, p < 0.0001) versus controls (14.02 μm) (Figure 3A and 3B). To understand if the thickening of the IFE was due to increased proliferation in the basal layer, we measured the proliferation index using Ki-67 immunohistochemistry. The proliferation index was markedly elevated in both iK5-TERT mice (8.2 Ki-67+ cells per 100 μm, 46.5% Ki-67+ cells among basal cells of IFE, p < 0.01) and in iK5-TERTci mice (12.2 per 100 μm, 63.1% among basal IFE, p < 0.0005) versus controls (2.8 per 100 μm, 7.9% among basal IFE) (Figure 3C–3F). The larger effects of TERTci compared to wild-type TERT on IFE thickness and proliferation index are likely due to variables intrinsic to comparing transgenic founder lines, such as expression level and variegation differences (unpublished data). Interestingly, Keratin 14-positive layer of the IFE was markedly expanded in both iK5-TERT mice and iK5-TERTci mice, although Ki-67+ cells were mostly confined in the basal monolayer (Figure 3E). These data indicate that the effects of TERT overexpression on skin extend beyond activation of bulge stem cells and include stimulation of progenitors in the basal layer of IFE.


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)

Both TERT and TERTci Enhance Proliferation of Interfollicular Epidermis in Mouse Skin(A) Expression of either TERT or TERTci increases thickness of interfollicular epidermis (IFE; black arrows). Dorsal skins were biopsied at days 55–60 and stained with H&E. Controls include non-transgenic and single-transgenic mice.(B) Quantification shows significant thickening of IFE in both iK5-TERT and iK5-TERTci (12 control, eight iK5-TERT, and 14 iK5-TERTci mice were analyzed. p < 0.00001 by one-way ANOVA and p < 0.05 by Student's t-test between control and iK5-TERT).(C,E) Expression of either TERT or TERTci increases proliferation in the basal layer of IFE. Abundance of Ki-67+ cells is increased in IFE of iK5-TERT and iK5-TERTci mice at days 55–60. Ki-67+ cells are stained by DAB (C) (black arrows), hematoxylin counterstain. Double immunostaining for Keratin 14 and Ki-67 (E). Green, K14; Red, Ki-67.(D,F) Quantification of Ki-67 staining shows significant increase in proliferation index. (D) Number of Ki-67+ cells per 100 μm. (F) Percentage of Ki-67+ cells within the basal layer of IFE (p < 0.0001 by one-way ANOVA and p < 0.01 by Student's t-test between control and iK5-TERT).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211538&req=5

pgen-0040010-g003: Both TERT and TERTci Enhance Proliferation of Interfollicular Epidermis in Mouse Skin(A) Expression of either TERT or TERTci increases thickness of interfollicular epidermis (IFE; black arrows). Dorsal skins were biopsied at days 55–60 and stained with H&E. Controls include non-transgenic and single-transgenic mice.(B) Quantification shows significant thickening of IFE in both iK5-TERT and iK5-TERTci (12 control, eight iK5-TERT, and 14 iK5-TERTci mice were analyzed. p < 0.00001 by one-way ANOVA and p < 0.05 by Student's t-test between control and iK5-TERT).(C,E) Expression of either TERT or TERTci increases proliferation in the basal layer of IFE. Abundance of Ki-67+ cells is increased in IFE of iK5-TERT and iK5-TERTci mice at days 55–60. Ki-67+ cells are stained by DAB (C) (black arrows), hematoxylin counterstain. Double immunostaining for Keratin 14 and Ki-67 (E). Green, K14; Red, Ki-67.(D,F) Quantification of Ki-67 staining shows significant increase in proliferation index. (D) Number of Ki-67+ cells per 100 μm. (F) Percentage of Ki-67+ cells within the basal layer of IFE (p < 0.0001 by one-way ANOVA and p < 0.01 by Student's t-test between control and iK5-TERT).
Mentions: Although the skin, or interfollicular epidermis (IFE), is repaired by progeny of hair follicle bulge stem cells during wounding, renewal of the IFE under homeostatic conditions is maintained by long-lived stem cells or progenitor cells in the basal layer of the IFE [28,29]. To determine if TERT affects progenitor cells in this basal layer, we examined the IFE in detail. The IFE was significantly thickened in both iK5-TERT mice (17.43 μm, p < 0.05) and in iK5-TERTci mice (24.33 μm, p < 0.0001) versus controls (14.02 μm) (Figure 3A and 3B). To understand if the thickening of the IFE was due to increased proliferation in the basal layer, we measured the proliferation index using Ki-67 immunohistochemistry. The proliferation index was markedly elevated in both iK5-TERT mice (8.2 Ki-67+ cells per 100 μm, 46.5% Ki-67+ cells among basal cells of IFE, p < 0.01) and in iK5-TERTci mice (12.2 per 100 μm, 63.1% among basal IFE, p < 0.0005) versus controls (2.8 per 100 μm, 7.9% among basal IFE) (Figure 3C–3F). The larger effects of TERTci compared to wild-type TERT on IFE thickness and proliferation index are likely due to variables intrinsic to comparing transgenic founder lines, such as expression level and variegation differences (unpublished data). Interestingly, Keratin 14-positive layer of the IFE was markedly expanded in both iK5-TERT mice and iK5-TERTci mice, although Ki-67+ cells were mostly confined in the basal monolayer (Figure 3E). These data indicate that the effects of TERT overexpression on skin extend beyond activation of bulge stem cells and include stimulation of progenitors in the basal layer of IFE.

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