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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Mmp23b promotes liver development and hepatocyte proliferation through the tumor necrosis factor pathway in zebrafish.
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Mmp23b promotes liver development and hepatocyte proliferation through the tumor necrosis factor pathway in zebrafish.

机译:Mmp23b通过斑马鱼中的肿瘤坏死因子途径促进肝脏发育和肝细胞增殖。

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摘要

The matrix metalloproteinase (MMP) family of proteins degrades extracellular matrix (ECM) components as well as processes cytokines and growth factors. MMPs are involved in regulating ECM homeostasis in both normal physiology and disease pathophysiology. Here we report the critical roles of mmp23b in normal zebrafish liver development. Mmp23b was initially identified as a gene linked to the genomic locus of an enhancer trap transgenic zebrafish line in which green fluorescent protein (GFP) expression was restricted to the developing liver. Follow-up analysis of mmp23b messenger RNA (mRNA) expression confirmed its liver-specific expression pattern. Morpholino knockdown of mmp23b resulted in defective hepatocyte proliferation, causing a reduction in liver size while maintaining relatively normal pancreas and gut development. Genetically, we showed that mmp23b functions through the tumor necrosis factor (TNF) signaling pathway. Antisense knockdown of tnfa or tnfb in zebrafish caused similar reductions of liver size, whereas overexpression of tnfa or tnfb rescued liver defects in mmp23b morphants but not vice versa. Biochemically, MMP23B, the human ortholog of Mmp23b, directly interacts with TNF and mediates its release from the cell membrane in a cell culture system. Because mmp23b/MMP23B is highly conserved, our findings in zebrafish warrant further investigation of its role in regulating liver development in mammals.
机译:基质金属蛋白酶(MMP)家族的蛋白质降解细胞外基质(ECM)成分,并处理细胞因子和生长因子。 MMP在正常生理和疾病病理生理中均参与调节ECM稳态。在这里,我们报告了mmp23b在正常斑马鱼肝脏发育中的关键作用。最初将Mmp23b鉴定为与增强子捕获转基因斑马鱼品系的基因组基因座相关的基因,其中绿色荧光蛋白(GFP)的表达仅限于发育中的肝脏。 mmp23b信使RNA(mRNA)表达的后续分析证实了其肝特异性表达模式。 mmp23b的吗啉敲除导致肝细胞增殖不良,从而导致肝脏缩小,同时保持相对正常的胰腺和肠道发育。遗传上,我们表明mmp23b通过肿瘤坏死因子(TNF)信号通路起作用。斑马鱼中tnfa或tnfb的反义敲除导致肝脏大小的相似减少,而tnfa或tnfb的过表达挽救了mmp23b morphant中的肝脏缺陷,反之则不然。从生化角度看,Mmp23B(人类Mmp23b直系同源物)直接与TNF相互作用并介导其在细胞培养系统中从细胞膜释放。由于mmp23b / MMP23B是高度保守的,因此我们在斑马鱼中的发现值得进一步研究其在调节哺乳动物肝脏发育中的作用。

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