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 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.

The Stemness Gene Mex3A Is a Key Regulator of Neuroblast Proliferation During Neurogenesis

“…Mex3A appears crucial for the maintenance of the slowly cycling subpopulation of lgr5+ gut stem cells (Chatterji and Rustgi, 2018), and lgr5 absence in Mex3A −/− mice leads to growth retardation, postnatal mortality, and severe impairment of intestinal crypt development (Pereira et al, 2020). Recent data showed that MEX3A is up-regulated in glioblastoma specimens (Bufalieri et al, 2020).…”

“…In particular, human MEX3A is necessary to post-transcriptionally regulate the levels of CDX2 , mRNA coding for an intestinal transcription factor required in gastrointestinal homeostasis ( Pereira et al, 2013 ). Mex3A appears crucial for the maintenance of the slowly cycling subpopulation of lgr5+ gut stem cells ( Chatterji and Rustgi, 2018 ), and lgr5 absence in Mex3A –/– mice leads to growth retardation, postnatal mortality, and severe impairment of intestinal crypt development ( Pereira et al, 2020 ).…”

“…The role of mex3 genes in mammals is poorly understood, though several studies suggest its putative involvement in self-renewal/differentiation decisions with implications for stem cell and cancer biology. In particular, human MEX3A was shown to play a key function in gastrointestinal context by impairing intestinal differentiation and simultaneously promoting an increased expression of intestinal stem cells markers such as LGR5 , BML1 , and MS1 ( Pereira et al, 2013 , 2020 ). In mice, mex3A is expressed in the crypt base and labels a slowly cycling subpopulation of Lgr5+ intestinal stem cell population ( Barriga et al, 2017 ; Chatterji and Rustgi, 2018 ).…”

Intestinal epithelial plasticity and regeneration via cell dedifferentiation

“…In line with the idea that Mex3a high cells are LRCs, they are enriched in BMI1, Lrig1, Tert and Hopx and display a low proliferation. A recent study also confirmed the role of Mex3a in the maintenance of the Lgr5 + ISC pool and further showed that it does so possibly by suppressing PPARγ signaling (Pereira et al 2020 ). PPARγ-selective agonists reduce the number and size more markedly in Mex3a KO organoids than WT organoids, which are consistent with the observation that Mex3a downregulates PPARγ expression and high PPARγ signaling impairs Lgr5 + ISCs (Pereira et al 2020 ).…”

Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer

“…In addition, ISCs may originate from a possible dedifferentiation of TACs or Paneth cells into Lgr5+ cells in response to Wnt3A or irradiation [ 15 ]. Interestingly, it was also revealed that a pool of Lgr5+ cells expressing the RNA-binding protein Mex3a are crucial for maintaining the Lgr5+ ISC pool in case of injury [ 16 ].…”