Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation
Year: 2017
Type: article
Abstract: Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body. Gpr182 knockdown had no effect on homeostatic intestinal proliferation in vivo, but led to marked increases in proliferation during intestinal regeneration following irradiation-induced injury. In the ApcMin mouse model, which forms spontaneous intestinal adenomas, reductions in Gpr182 led to more adenomas and decreased survival. Loss of Gpr182 enhanced organoid growth efficiency ex vivo in an EGF-dependent manner. Gpr182 reduction led to increased activation of ERK1/2 in basal and challenge models, demonstrating a potential role for this orphan GPCR in regulating the proliferative capacity of the intestine. Importantly, GPR182 expression was profoundly reduced in numerous human carcinomas, including colon adenocarcinoma. Together, these results implicate Gpr182 as a negative regulator of intestinal MAPK signaling-induced proliferation, particularly during regeneration and adenoma formation.
DOI: 10.1172/jci87588
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Breast Cancer Research Foundation, National Institutes of Health, Gillings School of Public Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
Awards: G1017297203, G1569999668, G1715857622, Intestinal Adaptation-Role of Hormones and Growth Factors, G1837376223, G2110504161, G2123418183, G2765941256, Causes and Consequences of Digestive Tract Lymphangiectasia, G402423035, Genetic Control of Intestinal Epithelial Stem Cell Maintenance & Differentiation, G589634768, G6534854312, G817157028, G9000073604, G9000083219, G9000101251, G9000126277, G9000167020, G9000182874, G9000218517, G9000239169, G9000324330, Center for Gastrointestinal Biology and Disease, UNC Center for Environmental Health and Susceptibility, Cancer Center Support Grant
OpenAlex ID: W2573337137