Wnt signaling is boosted during intestinal regeneration by a CD44-positive feedback loop

Walter, R. J. et al. (2022) Wnt signaling is boosted during intestinal regeneration by a CD44-positive feedback loop. Cell Death and Disease, 13(2), 168. (doi: 10.1038/s41419-022-04607-0) (PMID:35190527) (PMCID:PMC8861016)

Abstract

Enhancement of Wnt signaling is fundamental for stem cell function during intestinal regeneration. Molecular modules control Wnt activity by regulating signal transduction. CD44 is such a positive regulator and a Wnt target gene. While highly expressed in intestinal crypts and used as a stem cell marker, its role during intestinal homeostasis and regeneration remains unknown. Here we propose a CD44 positive-feedback loop that boosts Wnt signal transduction, thus impacting intestinal regeneration. Excision of Cd44 in Cd44fl/fl;VillinCreERT2 mice reduced Wnt target gene expression in intestinal crypts and affected stem cell functionality in organoids. Although the integrity of the intestinal epithelium was conserved in mice lacking CD44, they were hypersensitive to dextran sulfate sodium, and showed more severe inflammation and delayed regeneration. We localized the molecular function of CD44 at the Wnt signalosome, and identified novel DVL/CD44 and AXIN/CD44 complexes. CD44 thus promotes optimal Wnt signaling during intestinal regeneration.

• Item Type: Articles
• Additional Information: This work was supported by the Deutsche Forschungsgemeinschaft (Grant Number OR124/12–2) and by CRUK core funding to the CRUK Beatson Institute (A17196) and to OJS (A21139) (OJS and MH). MH was supported by an MRC PhD studentship MR/J50032X/1. Open Access funding enabled and organized by Projekt DEAL.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ridgway, Dr Rachel and Sansom, Professor Owen and Hodder, Michael
• Authors: Walter, R. J., Sonnentag, S. J., Munoz-Sagredo, L., Merkel, M., Richert, L., Bunert, F., Heneka, Y. M., Loustau, T., Hodder, M., Ridgway, R. A., Sansom, O. J., Mely, Y., Rothbauer, U., Schmitt, M., and Orian-Rousseau, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Disease
• Publisher: Springer Nature
• ISSN: 2041-4889
• ISSN (Online): 2041-4889
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Cell Death and Disease 13(2): 168
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190394		MRC Doctoral Training Grant 2011-2015	Mary Beth Kneafsey	Medical Research Council (MRC)	MR/J50032X/1	Research and Innovation Services