Mmp23b promotes liver development and hepatocyte proliferation through the tumor necrosis factor pathway in zebrafish.
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.
Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Ministry of Education, Beijing, China.
Fei
F
Qi
Jianbo
J
Song
Hanshuo
H
Yang
Wei
W
Gao
Ning-ai
NA
Liu
Bo
B
Zhang
Shuo
S
Lin
D000818:Animals; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000254:growth & development*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000494:pharmacology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D029961:Zebrafish Proteins; C117705:MMP23B protein, human; D020782:Matrix Metalloproteinases; C554847:mmp23ba protein, zebrafish