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

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

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages593-607
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number2
DOIs
StatePublished - Feb 1 2017

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Orphaned Children
Adenoma
Regeneration
Stem Cells
Organoids
Epidermal Growth Factor
Small Intestine
Intestines
Colon
Adenocarcinoma
Pharmacology
Carcinoma
Survival
Wounds and Injuries
Growth
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kechele, D. O., Blue, R. E., Zwarycz, B., Espenschied, S. T., Mah, A. T., Siegel, M. B., ... Caron, K. M. (2017). Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. Journal of Clinical Investigation, 127(2), 593-607. DOI: 10.1172/JCI87588

Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. / Kechele, Daniel O.; Blue, R. Eric; Zwarycz, Bailey; Espenschied, Scott T.; Mah, Amanda T.; Siegel, Marni B.; Perou, Charles M.; Ding, Shengli; Magness, Scott T.; Lund, P. Kay; Caron, Kathleen M.

In: Journal of Clinical Investigation, Vol. 127, No. 2, 01.02.2017, p. 593-607.

Research output: Research - peer-reviewArticle

Kechele DO, Blue RE, Zwarycz B, Espenschied ST, Mah AT, Siegel MB et al. Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. Journal of Clinical Investigation. 2017 Feb 1;127(2):593-607. Available from, DOI: 10.1172/JCI87588
Kechele, Daniel O. ; Blue, R. Eric ; Zwarycz, Bailey ; Espenschied, Scott T. ; Mah, Amanda T. ; Siegel, Marni B. ; Perou, Charles M. ; Ding, Shengli ; Magness, Scott T. ; Lund, P. Kay ; Caron, Kathleen M./ Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 2. pp. 593-607
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