LGR5 controls extracellular matrix production by stem cells in the developing intestine

The Lgr5 receptor is a marker of intestinal stem cells (ISCs) that regulates Wnt/b-catenin signaling. In this study, phenotype analysis of knockin/knockout Lgr5-eGFP-IRES-Cre and Lgr5-DTReGFPembryos reveals that Lgr5 deficiency during Wnt-mediated cytodifferentiation results in amplification ofISCs and early differentiation into Paneth cells, which can be counteracted byin uterotreatment with the Wnt inhibitorLGK974. Conditional ablation of Lgr5 postnatally, but not in adults, alters stem cell fate toward the Paneth lineage. Together, thesein vivostudies suggest that Lgr5 is part of a feedback loop to adjust the Wnt tone inISCs. Moreover, transcriptome analyses reveal that Lgr5 controls fetalISCmaturation associated with acquisition of a definitive stable epithelial phenotype, as well as the capacity ofISCs to generate their own extracellular matrix. Finally, using theex vivoculture system, evidences are provided that Lgr5 antagonizes the Rspondin 2-Wnt-mediated response inISCs in organoids, revealing a sophisticated regulatory process for Wnt signaling inISCs.