Expression of GPR182 in crypt cells is a switch for intestinal proliferation

Originally misidentified as an adrenomedullin receptor, recent observations have revealed that the orphan receptor GPR182 is expressed in stem cells in the crypt base of the gastrointestinal tract. This week in the JCI, work led by Kathleen Caron at the University of North Carolina has investigated the function of GPR182 in these crypt base stem cells, a population notable for high rates of proliferation. Although Gpr182 knockdown did not affect basal intestinal proliferation in mice, loss of Gpr182 was associated with increased proliferation following intestinal injury as well as increased tumor formation in a mouse model of intestinal adenoma. The researchers determined that loss of Gpr182 led to enhanced ERK1/2 activation, suggesting that GPR182 interacts with ERK signaling to regulate intestinal proliferation during regeneration and adenoma formation. These results identify GPR182 as a new potential target of therapies for gastrointestinal cancer.

The accompanying image shows a cross-section of a mouse intestine. Non-specific staining of mucous and microbiome make the intestinal lumen visible in the green center of the image.  Intestinal villi encircle the lumen, with cell nuclei shown in red and GPR182 expression, localized to stem cells, indicated in green. Lymphatic vessels are indicated in blue. 

Published January 17, 2017, by Elyse Dankoski

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Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation
Daniel O. Kechele, … , P. Kay Lund, Kathleen M. Caron
Daniel O. Kechele, … , P. Kay Lund, Kathleen M. Caron
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):593-607. https://doi.org/10.1172/JCI87588.
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Research Article Gastroenterology

Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation

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.

Authors

Daniel O. Kechele, R. Eric Blue, Bailey Zwarycz, Scott T. Espenschied, Amanda T. Mah, Marni B. Siegel, Charles M. Perou, Shengli Ding, Scott T. Magness, P. Kay Lund, Kathleen M. Caron

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