Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche

Abstract

Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR−/− telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium. Here we show that late-generation mTR−/− mutants experience marked downregulation of Wnt pathway genes in intestinal crypt epithelia, including crypt base columnar stem cells and Paneth cells, and in underlying stroma. The importance of these changes was revealed by rescue of crypt apoptosis and Wnt pathway gene expression upon treatment with Wnt pathway agonists. Rescue was associated with reduced telomere-dysfunction-induced foci and anaphase bridges, indicating improved telomere capping. Thus a mutually reinforcing feedback loop exists between telomere capping and Wnt signalling, and telomere capping can be impacted by extracellular cues in a fashion independent of telomerase.

Non-canonical Roles of Telomerase: Unraveling the Imbroglio

“…Pharmacological treatments that restored expression of components of the WNT pathway as well as one of the WNT targets in the epithelium of hTR −/− also restored telomere capping in the mutant epithelium. Importantly, this improved telomere capping was explained by the restoration of shelterin protein expression, including TRF2 and Pot1a rather than by telomere lengthening (Yang et al, 2017). This result was consistent with a previous study showing that TRF2 was transcriptionally activated by the Wnt/β-catenin signaling pathway in mouse intestinal tissues (Diala et al, 2013).…”

“…It turned out that in a more recent article, late-generation hTR −/− mice were shown to exhibit downregulation of either factor involved of the canonical WNT signaling, or targets of WNT pathway in the intestinal crypt epithelia (Yang et al, 2017). Pharmacological treatments that restored expression of components of the WNT pathway as well as one of the WNT targets in the epithelium of hTR −/− also restored telomere capping in the mutant epithelium.…”

The Potential Role of Cycloastragenol in Promoting Diabetic Wound Repair In Vitro

“…Researchers have suggested that the Wnt/beta-catenin pathway is involved in inflammatory response to diabetic ulcers, wound proliferation, wound remodeling, and stem cells [4]. In a prospective, randomized, controlled animal study, Yang and colleagues found that a lack of telomerase in mice was invariably associated with inhibited activation of Wnt/ β-catenin signaling, which could be improved with the administration of Wnt activator [11]. e data from their study suggest a potential relationship between telomerase and Wnt/β-catenin signaling.…”

Diverse mechanisms for endogenous regeneration and repair in mammalian organs

“…The cell-intrinsic mechanisms driving stem cell aging include loss of telomeres, epigenetic changes 68 , decline in mitochondrial function 69 and accumulation of DNA mutations 70 . In the intestine it has been shown that critical telomere shortening inactivates Wnt, which results in stem cell failure 71 . The cellular safeguards to cancer, including programmed cell death, senescence and differentiation, might be responsible for reduced stem cell number and activity as we age.…”