MEX3A Regulates Lgr5 + Stem Cell Maintenance in the Developing Intestinal Epithelium

Authors and Affiliations:

Bruno Pereira ^*,1,2, Ana L Amaral^1,2,‡, Alexandre Dias^1,2,‡, Nuno Mendes^1,2, Vanesa Muncan³, Ana R Silva^1,2, Chantal Thibert⁴, Anca G Radu⁴, Leonor David^1,2,5, Valdemar Máximo^1,2,5, Gijs R van den Brink^3,6, Marc Billaud⁷ and Raquel Almeida ^*,1,2,5,8

¹i3S ‐ Institute for Research and Innovation in Health (Instituto de Investigação e Inovação em Saúde), University of Porto, Porto, Portugal

²IPATIMUP ‐ Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal

³Department of Gastroenterology and Hepatology, Amsterdam UMC, Tytgat Institute, University of Amsterdam, Amsterdam, The Netherlands

⁴Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France

⁵FMUP‐Faculty of Medicine, University of Porto, Porto, Portugal

⁶Medicines Research Center, GSK, Stevenage, UK

⁷Clinical and Experimental Model of Lymphomagenesis, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France

⁸Biology Department, Faculty of Sciences, University of Porto, Porto, Portugal

^‡These authors contributed equally to this work

Abstract:

Intestinal stem cells (ISCs) fuel the lifelong self-renewal of the intestinal tract and are paramount for epithelial repair. In this context, the Wnt pathway component LGR5 is the most consensual ISC marker to date. Still, the effort to better understand ISC identity and regulation remains a challenge. We have generated a Mex3a knockout mouse model and show that this RNA-binding protein is crucial for the maintenance of the Lgr5+ ISC pool, as its absence disrupts epithelial turnover during postnatal development and stereotypical organoid maturation ex vivo. Transcriptomic profiling of intestinal crypts reveals that Mex3a deletion induces the peroxisome proliferator-activated receptor (PPAR) pathway, along with a decrease in Wnt signalling and loss of the Lgr5+ stem cell signature. Furthermore, we identify PPARγ activity as a molecular intermediate of MEX3A-mediated regulation. We also show that high PPARγ signalling impairs Lgr5+ ISC function, thus uncovering a new layer of post-transcriptional regulation that critically contributes to intestinal homeostasis.

Journal: EMBO Reports

Link: https://www.embopress.org/doi/full/10.15252/embr.201948938