Telomerase function in epithelial development and tumorigenesis.

摘要

Telomerase is expressed in embryonic tissues, adult progenitor cells and cancer cells, where it serves to support proliferation through lengthening telomeres, as well as through a novel pathway whose mechanism is poorly understood. In this work, we investigate the mechanism of this telomere-independent function of TERT, identify a novel function of TERT essential for hair follicle morphogenesis, and determine the role of TERT in epithelial tumorigenesis.;Ectopic expression of TERT in skin activates hair follicle stem cells, initiates a new hair follicle cycle, and promotes hair growth. However, the mechanism underlying this was unclear. By expressing a TERT mutant lacking reverse transcriptase function in mouse skin, we show that the catalytic activity of TERT is not responsible for this hair follicle phenotype. Instead, TERT orchestrates transcription of a developmental program that significantly resembles those of Myc and Wnt, pathways important for stem cell function and cancer. These findings suggest TERT as a dual-function protein which not only lengthens telomeres but also acts as a developmental regulator via the Myc and Wnt signaling networks.;While increasing number of evidence suggested the connection between TERT and signaling pathways crucial for normal development, study of TERT function has been hampered by lack of phenotype in germline TERT knockout mice. Surprisingly, we find that acute loss of TERT in neonatal mouse skin abrogates hair follicle morphogenesis. Upon conditional deletion of TERT, cells in bulge stem cell and bulb progenitor cell compartments undergo apoptosis, resulting in regression of hair follicles. The effect of TERT deletion phenocopies acute loss of beta-catenin, and both TERT and beta-catenin are haploinsufficient upon conditional deletion; indeed, Wnt signaling is diminished after acute TERT knockout. TERT directly targets Lef1, a critical activator of Wnt signaling, and transcriptionally regulates Lef1 and other key developmental genes. These data reveal an essential role for TERT in Wnt/beta-catenin signaling during hair follicle development that is masked in constitutive knockout mice through developmental compensation.;More interestingly, telomerase is not expressed in most adult tissues, but upregulated in about ninety percent of human cancer. Indeed, telomerase deficiency by knocking out TERC, telomere RNA template, confers resistance to chemical induction of papilloma, yet the mechanism underlying this is still unclear. Through extensive quantitative analysis of correlation between telomere characteristics and papilloma formation by using different-generation TERT knockout mice with various telomere settings, we find that critically short telomeres per se likely limit the formation of benign epithelial tumor. We propose that the contribution of TERT to premalignant tumor development is restricted to maintaining functional telomeres by lengthening critically short telomeres.;Overall, our data demonstrate two distinct functions of TERT and their implications in epithelial development and tumorigenesis. These findings call for a new perspective, and may pave the way for future investigations regarding TERT function in stem cells, progenitor cells and cancer.