Conditional telomerase induction causes proliferation of hair follicle stem cells - PubMed (original) (raw)

Conditional telomerase induction causes proliferation of hair follicle stem cells

Kavita Y Sarin et al. Nature. 2005.

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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Figure 1

Figure 1

Conditional activation of TERT promotes the anagen phase of the hair follicle cycle. a, Diagram of hair follicle cycling b, TRAP on Non-Tg skin samples at days 4, 10 (anagen-A), 16 (catagen-C), 19, 21 (telogen-T), 28, 34 (A), and 52 (T). c–d, Northern blot analysis and TRAP on skin extracts from i-TERT and WT mice at day 50. e, Non-Tg (+doxy) and i-TERT (+doxy) mice at day 70. f, H&E skin sections (*=telogen hair follicle, arrow= anagen hair follicle), 20x. g, RNA in situ hybridization for TERT mRNA and immunofluorescence for K14 in i-TERT (+doxy) skin (*=autofluorescence). h, RNA in situ hybridization for TERT mRNA (blue) in i-TERT(+doxy) skin section (right) and WT anagen skin (left) (*=dermal papilla).

Figure 2

Figure 2

TERT induction triggers a rapid transition from telogen to anagen. a, Northern blot (left) and TRAP assay (right) show increased TERT expression and telomerase activity by nine days of doxycycline treatment. b, Follicles in i-TERT mice entered anagen (arrow) by day 9, whereas Non-Tg controls remained in telogen (*), H&E, 20x. c, Hair growth was observed only in i-TERT mice (+doxy) (right), but not in i-TERT mice (−doxy) (center) or Non-Tg littermates (left).

Figure 3

Figure 3

TERT activates stem cells, depleting BrdU label from LRCs. a, Immunofluorescence for BrdU (red) and CD34 (green) shows maintenance of LRCs in Non-Tg group, but dramatic loss of label in i-TERT mice after doxy treatment (pre-doxy = day 55, post-doxy= day 90). b, Quantification of LRC data from (a), showing number of BrdU+ cells/CD34+ cells. i-TERT (black bars, n=4 mice), Non-Tg (gray bars, n=3 mice), - indicates pre-doxy, + indicates post-doxy. c, LRC analysis from whole mounts of epidermis from tail of mice labeled with BrdU at day 10, switched to doxy at day 40 and analyzed at day 65. (BrdU=red, K14=green). d, Immunofluorescence using Ki-67 (red) to mark proliferating cells and K14 (green) to identify basal layer of skin. e, Quantitation of proliferation index in (d) as Ki-67+ cells/100μm length of basal layer. n=2 mice for each comparison. f, GFP epifluorescence costained with CD34 (inset, confocal microscopy) in skin section from an actin-GFP mouse. g, RNA in situ analysis for TERT mRNA in i-TERT(+doxy) mouse skin. (inset) TERT mRNA expression (cytoplasmic) overlaps in bulge with LRCs, marked by BrdU (nuclear). h, H&E sections from K5tTA+; tetop-TERT+ (−doxy) (bottom) and Non-Tg (top) mice, 20X. Error bars indicate standard deviation. p values based on t-test. *=autofluorescence of hair.

Figure 4

Figure 4

TERT's activity in facilitating a transition from telogen to anagen is independent of its function in telomere synthesis. a, TERT induced anagen in mice with TERC+/+, TERC+/−, and TERC−/− backgrounds, H&E 20x. b, Skin samples from i-TERT; TERC−/− mice lacked telomerase activity by TRAP (left) and lacked TERC expression by RT-PCR (right).

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