Lgr4 is Required for Paneth Cell Differentiation and Maintenance of Intestinal Stem Cells Ex Vivo

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2011 Apr 22

PMID 21508962

Citations 76

Authors

Roxana C Mustata

Tom Van Loy

Anne Lefort

Frederick Libert

Sandra Strollo

Gilbert Vassart

Marie-Isabelle Garcia

Affiliations

Soon will be listed here.

Abstract

Gene inactivation of the orphan G protein-coupled receptor LGR4, 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.

Citing Articles

Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia.

Wong G, Hartmann S, Nonn O, Cannon P, Nguyen T, Kandel M Stem Cell Rev Rep. 2024; .

PMID: 39688759 DOI: 10.1007/s12015-024-10831-2.

Reprogramming human urine cells into intestinal organoids with long-term expansion ability and barrier function.

Zhang R, Chen Y, Feng Z, Cai B, Cheng Y, Du Y Heliyon. 2024; 10(13):e33736.

PMID: 39040281 PMC: 11261862. DOI: 10.1016/j.heliyon.2024.e33736.

Trophoblast Side-Population Markers are Dysregulated in Preeclampsia and Fetal Growth Restriction.

Wong G, Hartmann S, Simmons D, Ellis S, Nonn O, Cannon P Stem Cell Rev Rep. 2024; 20(7):1954-1970.

PMID: 39028417 PMC: 11445292. DOI: 10.1007/s12015-024-10764-w.

Ileal Crohn's Disease Exhibits Reduced Activity of Phospholipase C-β3-Dependent Wnt/β-Catenin Signaling Pathway.

Ando T, Takazawa I, Spencer Z, Ito R, Tomimori Y, Mikulski Z Cells. 2024; 13(11.

PMID: 38891118 PMC: 11171731. DOI: 10.3390/cells13110986.

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.

Malagola E, Vasciaveo A, Ochiai Y, Kim W, Zheng B, Zanella L Cell. 2024; 187(12):3056-3071.e17.

PMID: 38848678 PMC: 11164536. DOI: 10.1016/j.cell.2024.05.004.

References

Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z . Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009; 136(16):2747-56. PMC: 2730404. DOI: 10.1242/dev.033571. View

Andreu P, Peignon G, Slomianny C, Taketo M, Colnot S, Robine S . A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Dev Biol. 2008; 324(2):288-96. DOI: 10.1016/j.ydbio.2008.09.027. View

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View

Morita H, Mazerbourg S, Bouley D, Luo C, Kawamura K, Kuwabara Y . Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol. 2004; 24(22):9736-43. PMC: 525477. DOI: 10.1128/MCB.24.22.9736-9743.2004. View

Hsu S, Liang S, Hsueh A . Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol. 1998; 12(12):1830-45. DOI: 10.1210/mend.12.12.0211. View

Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, Vassart G . Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol. 2006; 290(2):421-34. DOI: 10.1016/j.ydbio.2005.11.043. View

Scoville D, Sato T, He X, Li L . Current view: intestinal stem cells and signaling. Gastroenterology. 2008; 134(3):849-64. DOI: 10.1053/j.gastro.2008.01.079. View

Kato S, Matsubara M, Matsuo T, Mohri Y, Kazama I, Hatano R . Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice. Nephron Exp Nephrol. 2006; 104(2):e63-75. DOI: 10.1159/000093999. View

Fodde R, Brabletz T . Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007; 19(2):150-8. DOI: 10.1016/j.ceb.2007.02.007. View

10.

Garcia M, Ghiani M, Lefort A, Libert F, Strollo S, Vassart G . LGR5 deficiency deregulates Wnt signaling and leads to precocious Paneth cell differentiation in the fetal intestine. Dev Biol. 2009; 331(1):58-67. DOI: 10.1016/j.ydbio.2009.04.020. View

11.

Mazerbourg S, Bouley D, Sudo S, Klein C, Zhang J, Kawamura K . Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol. 2004; 18(9):2241-54. DOI: 10.1210/me.2004-0133. View

12.

Potten C, Gandara R, Mahida Y, Loeffler M, Wright N . The stem cells of small intestinal crypts: where are they?. Cell Prolif. 2009; 42(6):731-50. PMC: 6496740. DOI: 10.1111/j.1365-2184.2009.00642.x. View

13.

Barker N, Clevers H . Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology. 2010; 138(5):1681-96. DOI: 10.1053/j.gastro.2010.03.002. View

14.

van der Flier L, van Gijn M, Hatzis P, Kujala P, Haegebarth A, Stange D . Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009; 136(5):903-12. DOI: 10.1016/j.cell.2009.01.031. View

15.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

16.

Powell D, Pinchuk I, Saada J, Chen X, Mifflin R . Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol. 2010; 73:213-37. PMC: 3754809. DOI: 10.1146/annurev.physiol.70.113006.100646. View

17.

Leighton P, Mitchell K, Goodrich L, Lu X, Pinson K, Scherz P . Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001; 410(6825):174-9. DOI: 10.1038/35065539. View

18.

Bjerknes M, Cheng H . Gastrointestinal stem cells. II. Intestinal stem cells. Am J Physiol Gastrointest Liver Physiol. 2005; 289(3):G381-7. DOI: 10.1152/ajpgi.00160.2005. View

19.

Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J . Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci U S A. 2008; 105(16):6081-6. PMC: 2329706. DOI: 10.1073/pnas.0708257105. View

20.

Zhu L, Gibson P, Currle D, Tong Y, Richardson R, Bayazitov I . Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. 2008; 457(7229):603-7. PMC: 2633030. DOI: 10.1038/nature07589. View