title: Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection.
abstract: Intestinal adaptation is an important compensatory response to massive small bowel resection (SBR) and occurs because of a proliferative stimulus to crypt enterocytes by poorly understood mechanisms. Recent studies suggest the enteric nervous system (ENS) influences enterocyte proliferation. We, therefore, sought to determine whether ENS dysfunction alters resection-induced adaptation responses. Ret+/- mice with abnormal ENS function and wild-type (WT) littermates underwent sham surgery or 50% SBR. After 7 days, ileal morphology, enterocyte proliferation, apoptosis, and selected signaling proteins were characterized. Crypt depth and villus height were equivalent at baseline in WT and Ret+/- mice. In contrast after SBR, Ret+/- mice had longer villi (Ret+/- 426.7 ± 46.0 μm vs. WT 306.5 ± 7.7 μm, P < 0.001) and deeper crypts (Ret+/- 119 ± 3.4 μm vs. WT 82.4 ± 3.1 μm, P < 0.001) than WT. Crypt enterocyte proliferation was higher in Ret+/- (48.8 ± 1.3%) than WT (39.9 ± 2.1%; P < 0.001) after resection, but apoptosis rates were similar. Remnant bowel of Ret+/- mice also had higher levels of glucagon-like peptide 2 (6.2-fold, P = 0.005) and amphiregulin (4.6-fold, P < 0.001) mRNA after SBR, but serum glucagon-like peptide 2 protein levels were equal in WT and Ret+/- mice, and there was no evidence of increased c-Fos nuclear localization in submucosal neurons. Western blot confirmed higher crypt epidermal growth factor receptor (EGFR) protein levels (1.44-fold; P < 0.001) and more phosphorylated EGFR (2-fold; P = 0.003) in Ret+/- than WT mice after SBR. These data suggest that Ret heterozygosity enhances intestinal adaptation after massive SBR, likely via enhanced EGFR signaling. Reducing Ret activity or altering ENS function may provide a novel strategy to enhance adaptation attenuating morbidity in patients with short bowel syndrome.
authors.affiliation: Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO 63110, USA.
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Hitch
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leinicke
authors.forename: Derek
authors.initials: D
authors.lastname: Wakeman
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Chris R
authors.initials: CR
authors.lastname: Erwin
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Rowland
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Merrick
authors.forename: Robert O
authors.initials: RO
authors.lastname: Heuckeroth
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D017615:Enteric Nervous System / Q000502:physiology; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism; D053767:Glucagon-Like Peptide 2 / Q000032:analysis; D006023:Glycoproteins / Q000032:analysis; D006579:Heterozygote; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D007420:Intestine, Large / Q000601:surgery; D007421:Intestine, Small / Q000294:innervation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000502:physiology; D012778:Short Bowel Syndrome / Q000601:surgery
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D053767:Glucagon-Like Peptide 2; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016760:Proto-Oncogene Proteins c-fos; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse