Dataset Information

MEX3A regulates Lgr5⁺ stem cell maintenance in the developing intestinal epithelium.

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 PPAR? activity as a molecular intermediate of MEX3A-mediated regulation. We also show that high PPAR? signalling impairs Lgr5⁺ ISC function, thus uncovering a new layer of post-transcriptional regulation that critically contributes to intestinal homeostasis.

SUBMITTER: Pereira B

PROVIDER: S-EPMC7132344 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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MEX3A regulates Lgr5<sup>+</sup> stem cell maintenance in the developing intestinal epithelium.

Pereira Bruno B Amaral Ana L AL Dias Alexandre A Mendes Nuno N Muncan Vanesa V Silva Ana R AR Thibert Chantal C Radu Anca G AG David Leonor L Máximo Valdemar V van den Brink Gijs R GR Billaud Marc M Almeida Raquel R

EMBO reports 20200213 4

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<sup>+</sup> ISC pool, as its absence disrupts epithelial turnover d ...[more]

PMID: 32052574

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Project description:The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Dataset Information

MEX3A regulates Lgr5⁺ stem cell maintenance in the developing intestinal epithelium.

Publications

MEX3A regulates Lgr5<sup>+</sup> stem cell maintenance in the developing intestinal epithelium.

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Dataset Information

MEX3A regulates Lgr5+ stem cell maintenance in the developing intestinal epithelium.

Publications

MEX3A regulates Lgr5<sup>+</sup> stem cell maintenance in the developing intestinal epithelium.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MEX3A regulates Lgr5⁺ stem cell maintenance in the developing intestinal epithelium.