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

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.

Wnt signaling regulates homeostasis of the periodontal ligament

“…Aging is obviously a complex process (50) but there is accumulating evidence to support the theory that some of these age-related atrophic changes in mineralized tissues are caused by a reduction in Wnt signal-ing. For example, there is a strong correlation between telomere length and biological age (51), and new data demonstrate that telomerase activity, which is essential for stabilizing and maintaining the length of telomeres, is regulated by Wnt signals (52)(53)(54)(55)(56). Conversely, diminished Wnt signaling is associated with abnormally short telomeres and the early onset of aging (54,57,58).…”

Dyskeratosis congenita

“…Telomerase synthesizes telomeric repeat sequences onto the telomeres. Telomerase is also thought to have extra-telomeric functions important in stem cell proliferation [14]. In humans after birth telomerase expression is confined to germ cells, stem cells and their immediate progeny, activated T cells, and monocytes: all other somatic cells lack telomerase activity or express telomerase only at very low levels.…”

Expression profiles of proliferative and antiapoptotic genes in sporadic and colitis‐related mouse colon cancer models

“…ranges are denoted by small squares, boxes and bars respectively. Significant differences between neoplastic cells and surrounding normal epithelial cells: *P < 0.001; **P < 0.05. cell growth but that TERT is also able to activate progenitor cells by controlling Myc-and Wnt-related transcription pathways (Choi et al 2008). This idea is supported by the finding that c-Myc is a known target of the Wnt pathway and is a downstream signal controlling intestinal proliferation (Sansom et al 2007).…”