RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells

RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells

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 enterocolit...

Full description

Saved in:
Bibliographic Details
Published in:Gastroenterology (New York, N.Y. 1943) Vol. 166; no. 3; pp. 437 - 449
Main Authors: Shepherd, Amy, Feinstein, Laurence, Sabel, Svetlana, Rastelli, Daniella, Mezhibovsky, Esther, Matthews, Lynley, Muppirala, Anoohya, Robinson, Ariel, Sharma, Karina R., ElSeht, Abrahim, Zeve, Daniel, Breault, David T., Gershon, Michael D., Rao, Meenakshi
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-03-2024
Subjects:
Animals
Enteric Nervous System
Enteroendocrine Cells
Glucagon-Like Peptide 1
Hirschsprung Disease - genetics
Humans
Infant
Inhibitory Motor Neurons
Intestine, Small
Male
Mice
Neurotrophic Factor
Peptide YY
Proto-Oncogene Proteins c-ret - genetics
Serotonin
Sex Differences
CHGA
EEC
GI
Sex Differences
GITT
GLP-1
FPO
NPY2R
ENS
CFP
PYY
CALB1
ANOVA
HSCR
NOS1
Neurotrophic Factor
VIP
5-HT
Inhibitory Motor Neurons
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. RetCFP/+ 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. [Display omitted] Signaling by the RET growth factor receptor in intestinal epithelial cells is important for regulating gut hormone release and propulsive activity, offering a new therapeutic target for motility disorders.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0016-5085
1528-0012
DOI:10.1053/j.gastro.2023.11.020