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

Roxana C Mustata1, Tom Van Loy, Anne Lefort

  • 1Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Faculty of Medicine, Université Libre de Bruxelles, Route de Lennik 808, Brussels 1070, Belgium.

EMBO Reports
|April 22, 2011
PubMed

Insights

Gene inactivation of LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) severely impairs intestinal epithelial cell proliferation and differentiation. LGR4 is crucial for maintaining intestinal stem cells by acting as a permissive factor in the Wnt pathway.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Stem Cell Biology

Background:

  • Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is an orphan receptor and paralogue of LGR5, a known epithelial stem cell marker.
  • Intestinal crypts rely on stem cells for continuous epithelial renewal and differentiation of specialized cell types, including Paneth cells.
  • The Wnt signaling pathway is critical for maintaining intestinal stem cell populations and regulating crypt homeostasis.

Purpose of the Study:

  • To investigate the role of LGR4 in intestinal epithelial cell proliferation, differentiation, and stem cell maintenance.
  • To elucidate the relationship between LGR4 and the Wnt signaling pathway in the context of intestinal crypt biology.
  • To determine the therapeutic potential of targeting LGR4 in intestinal diseases, particularly cancer.

Main Methods:

  • Gene inactivation (knockout) of LGR4 in mouse models.
  • Ex vivo culture of LGR4-deficient and LGR5-deficient intestinal crypts and progenitor cells.
  • Assessment of cell proliferation and differentiation markers.
  • Analysis of stem cell markers and Wnt target gene expression.
  • Pharmacological manipulation using LiCl and Wnt agonists in cultured cells.

Main Results:

  • LGR4 gene inactivation led to a 50% decrease in epithelial cell proliferation and an 80% reduction in Paneth cell differentiation in postnatal mouse intestinal crypts.
  • LGR4-deficient crypts and progenitors exhibited rapid cell death ex vivo, accompanied by downregulation of stem cell markers and Wnt target genes, including Lgr5.
  • LGR5-deficient progenitors did not display the same rapid death phenotype.
  • Partial rescue of the LGR4-deficient phenotype was observed with LiCl treatment, but not with Wnt agonists.
  • These findings suggest LGR4 acts as a permissive factor in the Wnt pathway.

Conclusions:

  • LGR4 is essential for maintaining intestinal epithelial stem cell function and survival.
  • LGR4 plays a critical permissive role in Wnt pathway signaling within the intestinal crypt microenvironment.
  • LGR4 represents a potential therapeutic target for intestinal cancer, given its role in stem cell regulation and Wnt signaling.

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