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Nat Commun. 2017 Mar 17;8:14766. doi: 10.1038/ncomms14766.

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

Author information

1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Cell and Molecular Biology Program, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Penn Molecular Profiling Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4
Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
6
Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
7
Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
28303901
PMCID:
PMC5357864
DOI:
10.1038/ncomms14766
[Indexed for MEDLINE]
Free PMC Article

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