Journal article
RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells
Gastroenterology (New York, N.Y. 1943)
21 Nov 2023
PMID: 37995867
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
RET tyrosine kinase is necessary for enteric nervous system development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility.
Ret
mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET regulates gut motility in vivo, genetic, and pharmacologic approaches were used to disrupt RET in all RET-expressing cells, a subset of enteric neurons, or intestinal epithelial cells.
Distinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the epithelium, rather than in enteric neurons, slowed GI motility selectively in male mice. RET kinase inhibition phenocopied this effect. Most RET
epithelial cells were either enterochromaffin cells that release serotonin or L-cells that release peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), both of which can alter motility. RET kinase inhibition exaggerated PYY and GLP-1 release in a nutrient-dependent manner without altering serotonin secretion in mice and human organoids. PYY receptor blockade rescued dysmotility in mice lacking epithelial RET.
RET signaling normally limits nutrient-dependent peptide release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.
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Details
- Title
- RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells
- Creators
- Amy Shepherd - Boston Children's HospitalLaurence Feinstein - Columbia University Irving Medical CenterSvetlana Sabel - Columbia University Irving Medical CenterDaniella Rastelli - Boston Children's HospitalEsther Mezhibovsky - Columbia University Irving Medical CenterLynley Matthews - Columbia University Irving Medical CenterAnoohya Muppirala - Boston Children's HospitalAriel Robinson - Boston Children's HospitalKarina R Sharma - Boston Children's HospitalAbrahim ElSeht - Boston Children's HospitalDaniel Zeve - Boston Children's HospitalDavid T Breault - Boston Children's HospitalMichael D Gershon - Columbia University Irving Medical CenterMeenakshi Rao - Boston Children's Hospital
- Publication Details
- Gastroenterology (New York, N.Y. 1943)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:001202761700001
- Scopus ID
- 2-s2.0-85179332694
- Other Identifier
- 991021838156704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Gastroenterology & Hepatology