title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Cell and Molecular Biology Program, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ting-Lin B
authors.initials: TB
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Deng
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Geetha
authors.initials: G
authors.lastname: Jagannathan
authors.affiliation: Penn Molecular Profiling Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Tobias
authors.affiliation: Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lynch
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Cell and Molecular Biology Program, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015536:Down-Regulation; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D019879:Paneth Cells / Q000378:metabolism; D012313:RNA / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase