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

Ting Lin B. Yang, Qijun Chen, Jennifer T. Deng, Geetha Jagannathan, John W. Tobias, David C. Schultz, Shan Wang, Christopher J. Lengner, Anil K. Rustgi, John P. Lynch, F. Brad Johnson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number14766
JournalNature communications
Volume8
DOIs
StatePublished - Mar 17 2017
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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