Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo

Abstract

Gene inactivation of the orphan G protein-coupled receptorLGR4, a paralogue of the epithelial-stem-cell marker LGR5, results in a 50% decrease in epithelial cell proliferation and an 80% reduction in terminal differentiation of Paneth cells in postnatal mouse intestinal crypts. When cultured ex vivo, LGR4-deficient crypts or progenitors, but not LGR5-deficient progenitors, die rapidly with marked downregulation of stem-cell markers and Wnt target genes, including Lgr5. Partial rescue of this phenotype is achieved by addition of LiCl to the culture medium, but not Wnt agonists. Our results identify LGR4 as a permissive factor in the Wnt pathway in the intestine and, as such, as a potential target for intestinal cancer therapy.

Lgr4 Gene Deficiency Increases Susceptibility and Severity of Dextran Sodium Sulfate-induced Inflammatory Bowel Disease in Mice

“…4A). By using an unambiguous Paneth cell marker, we observed that the number of Paneth cells was 80 -85% lower in Lgr4 mutant mice when compared with WT mice, which is consistent with a previous study (27) (Fig. 4, B and C).…”

“…Because the Lgr4 mutant mouse model is different from the Paneth cell depletion models, we speculate that Lgr4 could regulate Bmi1 ϩ stem cell numbers, which was supported by Mustata et al (27), who demonstrated that the Bmi1 mRNA level was decreased in Lgr4 mutant crypts. Moreover, Yan et al (36) reported that Lgr5 ϩ ISCs were dependent on R-spondin1, which is also essential for in vitro culture of Bmi1 ϩ ISCs.…”

“…Lgr4 is required for Paneth cell differentiation and the maintenance of Lgr5 ϩ ISCs in normal conditions (26,27). Recently, several processes have been highlighted to be important to Paneth cell biology and susceptibility to IBD in both humans and …”

“…Recently, Lgr4 and its homologue Lgr5 have been identified as receptors of R-spondins, secreted Wnt pathway agonists and potentiators of Wnt/␤-catenin and Wnt/PCP signaling (14,26). In the intestine, Lgr4 is required for Paneth cell differentiation (27) and maintenance of intestinal stem cells (26). Here, we demonstrate that Lgr4-deficient mice are more susceptible to DSS-induced colitis.…”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…However, because the Wnt pathway drives the expression of several target genes in ISCs [20], the lack of expression of some targets is not equivalent to the lack of Wnt signaling. For example, Lgr5, the first Wnt target gene found to definitively mark the crypt base stem cells, is not required for stem cell maintenance [24,32]. Thus, the lack of expression of Lgr5 in tumor 'Lgr5 cell' signatures is unlikely to impact the stemness of those cells.…”