Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Ministry of Education, Beijing, China.
Hepatology. 2010 Dec;52(6):2158-66. doi: 10.1002/hep.23945. Epub 2010 Nov 9.
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.
基质金属蛋白酶（MMP）家族蛋白降解细胞外基质（ECM）成分以及处理细胞因子和生长因子。MMPs 参与调节正常生理和疾病病理生理学中 ECM 的动态平衡。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。Mmp23b 最初被鉴定为与增强子陷阱转基因斑马鱼系的基因组座位相关的基因，在该系中，绿色荧光蛋白（GFP）表达仅限于发育中的肝脏。对 mmp23b 信使 RNA（mRNA）表达的后续分析证实了其肝脏特异性表达模式。Mmp23b 的 Morpholino 敲低导致肝实质细胞增殖缺陷，导致肝脏大小减小，而胰腺和肠道发育相对正常。从遗传学上讲，我们表明 mmp23b 通过肿瘤坏死因子（TNF）信号通路发挥作用。在斑马鱼中反义敲低 tnfa 或 tnfb 导致肝脏大小相似的减小，而 tnfa 或 tnfb 的过表达挽救了 mmp23b 形态发生缺陷，但反之则不然。从生化上讲，Mmp23B，Mmp23b 的人类同源物，直接与 TNF 相互作用，并在细胞培养系统中介导其从细胞膜释放。由于 mmp23b/MMP23B 高度保守，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。
