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Liver-specific expression of p53-negative regulator mdm2 leads to growth retardation and fragile liver in zebrafish
Li-Je Chen1, Chia-Chun Hsu, Jiann-Ruey Hong
1Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
Abstract:
Tumorigenesis requires inactivation of the p53 tumor suppressor pathway, likely involving the negative regulator Mdm2 protein. To analyze the possible roles of Mdm2 in oncogenesis and other functions during zebrafish hepatogenesis, we generated transgenic zebrafish by liver-specific Mdm2 over-expression utilizing a fusion between genes encoding GFP and mdm2, GFP::Mdm2. Over-expression of GFP::Mdm2 in the zebrafish liver did not interrupt normal liver development in the larval stages but approximately 30% of the adult fish raised from the same larvae displayed obvious growth retardation at 16 weeks of age. Most growth-retarded adults displayed liver atrophy, contraction, or hypoplasia, which proved lethal within 4 to 8 months. Histologically, over-expression of GFP::Mdm2 in Gmdm2-liver leading to liver degeneration may in some way have been due to an increased cell apoptosis accompanied by a slightly interrupted cell cycle or hepatocyte proliferation. Liver degeneration or other transgenic phenotypes were not associated with liver cancer; however, liver-degenerated phenotypes could be passed to wild-type zebrafish. In this study, we generated transgenic zebrafish lines with a "fragile liver." The "fragile liver" zebrafish can provide a model for molecular pathology of liver diseases and for screening small molecules that affect mdm2-related pathways.
Insights
Over-expressing Mdm2 in zebrafish livers caused growth retardation and liver degeneration, creating a "fragile liver" model. This model aids in studying liver diseases and screening drugs targeting Mdm2 pathways.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Tumorigenesis often involves the p53 tumor suppressor pathway.
- Mdm2 protein is a known negative regulator of p53.
- Understanding Mdm2's role in liver development is crucial.
Purpose of the Study:
- To investigate the function of Mdm2 during zebrafish liver development.
- To create a transgenic zebrafish model for studying Mdm2-related liver pathologies.
- To assess the impact of Mdm2 over-expression on hepatogenesis and oncogenesis.
Main Methods:
- Generated transgenic zebrafish with liver-specific over-expression of GFP::Mdm2.
- Observed liver development and phenotypes from larval to adult stages.
- Performed histological analysis to examine cellular changes like apoptosis and cell cycle progression.
Main Results:
- Liver-specific Mdm2 over-expression did not affect larval liver development.
- Approximately 30% of adult fish exhibited growth retardation and lethal liver atrophy/hypoplasia.
- Hepatocyte apoptosis and cell cycle interruption were observed, but not liver cancer.
- Transgenic phenotypes, including liver degeneration, were heritable to wild-type offspring.
Conclusions:
- Mdm2 over-expression in zebrafish livers leads to a
- fragile liver
- phenotype.
- This zebrafish model is valuable for studying liver disease molecular pathology.
- The model can be used for screening small molecules targeting mdm2-related pathways.
