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.

中文翻译：

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MEX3A 调节发育中的肠上皮中 Lgr5+ 干细胞的维持。

肠道干细胞 (ISC) 促进肠道的终生自我更新，对上皮修复至关重要。在这种情况下，Wnt 通路成分 LGR5 是迄今为止最一致的 ISC 标记。尽管如此，更好地理解 ISC 身份和监管的努力仍然是一项挑战。我们已经生成了一个 Mex3a 敲除小鼠模型，并表明这种 RNA 结合蛋白对于维持 Lgr5+ ISC 池至关重要，因为它的缺失会破坏出生后发育和体外成熟类器官成熟过程中的上皮更新。肠隐窝的转录组分析表明，Mex3a 缺失诱导过氧化物酶体增殖物激活受体 (PPAR) 通路，同时 Wnt 信号传导减少和 Lgr5+ 干细胞特征丧失。此外，我们将 PPARγ 活性鉴定为 MEX3A 介导的调节的分子中间体。我们还表明，高 PPARγ 信号会损害 Lgr5+ ISC 功能，从而揭示了一个新的转录后调控层，它对肠道稳态至关重要。