Mmp23b Promotes Liver Development and Hepatocyte... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Mmp23b Promotes Liver Development and Hepatocyte Proliferation Through the Tumor Necrosis Factor Pathway in Zebrafish

Qi, Fei1,2,3; Song, Jianbo3; Yang, Hanshuo4; Gao, Wei1; Liu, Ning-ai5; Zhang, Bo1; Lin, Shuo1,2,3

1Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Ministry of Education, Beijing, China

2Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China

3Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA

4State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, China

5Department of Medicine, Cedars-Sinai Research Institute, University of California, Los Angeles, CA

Abbreviations: ECM, extracellular matrix; GFP, green ﬂuorescent protein; HSC, hepatic stellate cells; MMP, matrix metalloproteinase; MO, morpholino; RFP, red ﬂuorescent protein; TGF-b1, transforming growth factor-b1; TNF, tumor necrosis factor; WISH, whole-mount in situ hybridization.

Received February 16, 2010; accepted August 19, 2010.

Supported in part by grants from the National Institutes of Health to S.L. (RR13227, DK054508, HD061570), from NSFC (No. 30721064 and 30730056), as well as 973 Program from MOST of P.R. China (2005CB522504, 2006CB943801, 2007CB914502, and 2009CB941203).

F.Q. was supported in part by China Scholarship Council, Ministry of Education, China.

Potential conﬂict of interest: Nothing to report.

Correspondence Shuo Lin, Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095. E-mail: [email protected]; fax: (310) 267-4971.

Online date: November 9, 2010

Abstract

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 re-stricted 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 path-way. 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. (HEPATOLOGY 2010;52:2158-2166)