TY - JOUR
T1 - Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice
AU - Shinohara, Masahiko
AU - Mao, Maria
AU - Keeley, Theresa M.
AU - Elzaatari, Mohamad
AU - Lee, Hyukjoon
AU - Eaton, Kathryn A.
AU - Samuelson, Linda C.
AU - Merchant, Juanita L.
AU - Goldenring, James R.
AU - Todisco, Andrea
N1 - Funding Information: Funding Supported by NIDDK grant R56058312-06A2 (A.T.), grant PO1-DK-06204 (J.M.), grants RO1 DK56882 and RO1 DK78927 (L.S.), grant RO1 DK071590 (J.R.G.), the University of Michigan Gastrointestinal Peptide Research Center (grant P30-DK-34933 ), bridging funds (A.T.), and the Funderburg Award in Gastric Biology Related to Cancer (J.R.G.) from the Foundation for Digestive Health and Nutrition , and by a Department of Veterans Affairs Merit Review Award (J.R.G.).
PY - 2010/12
Y1 - 2010/12
N2 - Background & Aims We investigated the role of bone morphogenetic protein (BMP) signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach. Methods The promoter of the mouse H+/K+-ATPase β-subunit gene, which is specifically expressed in parietal cells, was used to regulate expression of noggin in the gastric epithelium of mice. The transgenic mice were analyzed for noggin expression, tissue morphology, cellular composition of the gastric mucosa, gastric acid content, and plasma levels of gastrin. Tissues were analyzed by immunohistochemical, quantitative real-time polymerase chain reaction, immunoblot, microtitration, and radioimmunoassay analyses. Results In the stomachs of the transgenic mice, phosphorylation of Smad 1, 5, and 8 decreased, indicating inhibition of BMP signaling. Mucosa were of increased height, with dilated glands, cystic structures, reduced numbers of parietal cells, and increased numbers of cells that coexpressed intrinsic factor, trefoil factor 2, and Griffonia (Bandeiraea) simplicifolia lectin II, compared with wild-type mice. In the transgenic mice, levels of the H+/K+-ATPase α-subunit protein and messenger RNA were reduced, whereas those of intrinsic factor increased. The transgenic mice were hypochloridric and had an increased number of Ki67- and proliferating cell nuclear antigen-positive cells; increased levels of plasma gastrin; increased expression of transforming growth factor-α, amphiregulin, and gastrin; and activation of extracellular signal-regulated kinase 2. Conclusions Inhibiting BMP signaling in the stomachs of mice by expression of noggin causes loss of parietal cells, development of transitional cells that express markers of mucus neck and zymogenic lineages, and activation of proliferation. BMPs are therefore important regulators of gastric epithelial cell homeostasis.
AB - Background & Aims We investigated the role of bone morphogenetic protein (BMP) signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach. Methods The promoter of the mouse H+/K+-ATPase β-subunit gene, which is specifically expressed in parietal cells, was used to regulate expression of noggin in the gastric epithelium of mice. The transgenic mice were analyzed for noggin expression, tissue morphology, cellular composition of the gastric mucosa, gastric acid content, and plasma levels of gastrin. Tissues were analyzed by immunohistochemical, quantitative real-time polymerase chain reaction, immunoblot, microtitration, and radioimmunoassay analyses. Results In the stomachs of the transgenic mice, phosphorylation of Smad 1, 5, and 8 decreased, indicating inhibition of BMP signaling. Mucosa were of increased height, with dilated glands, cystic structures, reduced numbers of parietal cells, and increased numbers of cells that coexpressed intrinsic factor, trefoil factor 2, and Griffonia (Bandeiraea) simplicifolia lectin II, compared with wild-type mice. In the transgenic mice, levels of the H+/K+-ATPase α-subunit protein and messenger RNA were reduced, whereas those of intrinsic factor increased. The transgenic mice were hypochloridric and had an increased number of Ki67- and proliferating cell nuclear antigen-positive cells; increased levels of plasma gastrin; increased expression of transforming growth factor-α, amphiregulin, and gastrin; and activation of extracellular signal-regulated kinase 2. Conclusions Inhibiting BMP signaling in the stomachs of mice by expression of noggin causes loss of parietal cells, development of transitional cells that express markers of mucus neck and zymogenic lineages, and activation of proliferation. BMPs are therefore important regulators of gastric epithelial cell homeostasis.
KW - TFF2
KW - TGF
KW - Transforming Growth Factor α
KW - Trefoil Factor 2
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U2 - 10.1053/j.gastro.2010.08.052
DO - 10.1053/j.gastro.2010.08.052
M3 - Article
SN - 0016-5085
VL - 139
SP - 2050-2060.e2
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -