Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.
Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.
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DOI：
10.1053/j.gastro.2010.08.052
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发表时间：
2010-12
期刊：
影响因子：
29.4
通讯作者：
Todisco A
中科院分区：
文献类型：
--
作者：
Shinohara M;Mao M;Keeley TM;El-Zaatari M;Lee HJ;Eaton KA;Samuelson LC;Merchant JL;Goldenring JR;Todisco A
我们通过在胃中表达骨形态发生蛋白(BMP)抑制物noggin的转基因小鼠，研究了BMP信号在调节胃上皮细胞生长和分化中的作用。利用在壁细胞中特异表达的小鼠H+/K+-ATPaseβ亚单位基因启动子调控小鼠胃上皮细胞中noggin的表达。分析转基因小鼠的noggin表达、组织形态、胃粘膜细胞成分、胃酸含量和血浆胃泌素水平。采用免疫组织化学、实时定量聚合酶链式反应、免疫印迹、微量滴定和放射免疫分析等方法对组织进行分析。在转基因小鼠的胃中，Smad1、Smad5和Smad8的磷酸化水平降低，表明BMP信号受到抑制。与野生型小鼠相比，粘膜高度增加，腺体扩张，囊状结构，壁细胞数量减少，共表达内在因子、三叶因子2和单叶灰霉凝集素II的细胞数量增加。在转基因小鼠中，H+/K+-ATPaseα亚单位蛋白和信使核糖核酸水平降低，而内源性因子水平上升。转基因小鼠处于低氯化状态，Ki67和增殖细胞核抗原阳性细胞数量增加，血浆胃泌素水平升高，转化生长因子-α、双调节蛋白和胃泌素表达增加，细胞外信号调节激酶2激活。通过noggin表达抑制小鼠胃中的骨形态发生蛋白信号会导致壁细胞的丧失，表达粘液颈和产酶系标志的过渡细胞的发育，以及增殖的激活。因此，BMPS是胃上皮细胞动态平衡的重要调节因子。
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. 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. In the stomachs of the transgenic mice, phosphorylation of Smad1, 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 simplicifolialectin 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. 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.
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影响因子：
6.2
作者：
NAKASHIMA, H;INOUE, H;AKIYOSHI, T
通讯作者：
AKIYOSHI, T
DOI：
10.1152/ajpgi.00461.2005
发表时间：
2006-05-01
影响因子：
4.5
作者：
Lopez-Diaz, L;Hinkle, KL;Samuelson, LC
通讯作者：
Samuelson, LC
DOI：
10.1152/ajpgi.00187.2006
发表时间：
2006-12-01
影响因子：
4.5
作者：
Goldenring, James R.;Nomura, Sachiyo
通讯作者：
Nomura, Sachiyo
DOI：
10.1152/ajpgi.00194.2006
发表时间：
2007-09-01
影响因子：
4.5
作者：
Nitsche, Hildegard;Ramamoorthy, Saravanan;Todisco, Andrea
通讯作者：
Todisco, Andrea
DOI：
10.1152/ajpgi.00160.2004
发表时间：
2005-02-01
影响因子：
4.5
作者：
Nomura, S;Yamaguchi, H;Goldenring, JR
通讯作者：
Goldenring, JR