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Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
Identification of Annexin A4 as a hepatopancreas factor involved in liver cell survival
Danhua Zhang1, Vladislav S Golubkov2, Wenlong Han3
1Sanford Children's Health Research Center, Programs in Genetic Disease, Development and Aging, and Stem Cell and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA; Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Abstract:
To gain insight into liver and pancreas development, we investigated the target of 2F11, a monoclonal antibody of unknown antigen, widely used in zebrafish studies for labeling hepatopancreatic ducts. Utilizing mass spectrometry and in vivo assays, we determined the molecular target of 2F11 to be Annexin A4 (Anxa4), a calcium binding protein. We further found that in both zebrafish and mouse endoderm, Anxa4 is broadly expressed in the developing liver and pancreas, and later becomes more restricted to the hepatopancreatic ducts and pancreatic islets, including the insulin producing ß-cells. Although Anxa4 is a known target of several monogenic diabetes genes and its elevated expression is associated with chemoresistance in malignancy, its in vivo role is largely unexplored. Knockdown of Anxa4 in zebrafish leads to elevated expression of caspase 8 and Δ113p53, and liver bud specific activation of Caspase 3 and apoptosis. Mosaic knockdown reveal that Anxa4 is required cell-autonomously in the liver bud for cell survival. This finding is further corroborated with mosaic anxa4 knockout studies using the CRISPR/Cas9 system. Collectively, we identify Anxa4 as a new, evolutionarily conserved hepatopancreatic factor that is required in zebrafish for liver progenitor viability, through inhibition of the extrinsic apoptotic pathway. A role for Anxa4 in cell survival may have implications for the mechanism of diabetic ß-cell apoptosis and cancer cell chemoresistance.
Insights
Researchers identified Annexin A4 (Anxa4) as the target of antibody 2F11. Anxa4 is crucial for liver progenitor survival in zebrafish by inhibiting apoptosis, with potential links to diabetes and cancer.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Biology
Background:
- The monoclonal antibody 2F11 is widely used in zebrafish studies to label hepatopancreatic ducts, but its target antigen is unknown.
- Annexin A4 (Anxa4), a calcium-binding protein, is implicated in monogenic diabetes and cancer chemoresistance, yet its in vivo function remains largely unexplored.
Purpose of the Study:
- To identify the molecular target of the 2F11 antibody.
- To investigate the in vivo role of Annexin A4 (Anxa4) in liver and pancreas development.
Main Methods:
- Mass spectrometry to identify the antigen for 2F11.
- In vivo assays in zebrafish, including knockdown and CRISPR/Cas9 gene editing.
- Analysis of Anxa4 expression in zebrafish and mouse endoderm.
Main Results:
- The molecular target of 2F11 was identified as Annexin A4 (Anxa4).
- Anxa4 is broadly expressed in developing liver and pancreas, becoming restricted to ducts and islets, including beta-cells.
- Anxa4 knockdown in zebrafish induced apoptosis in liver progenitors by upregulating caspase 8 and caspase 3, indicating a cell-autonomous requirement for survival.
Conclusions:
- Annexin A4 (Anxa4) is a novel, evolutionarily conserved factor essential for hepatopancreatic duct development and liver progenitor viability in zebrafish.
- Anxa4 functions by inhibiting the extrinsic apoptotic pathway, ensuring cell survival.
- The findings suggest potential implications of Anxa4 in the mechanisms underlying diabetic beta-cell apoptosis and cancer cell chemoresistance.
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