PUBLICATION
Hypoxia-Inducible Factor 2 Alpha Is Essential for Hepatic Outgrowth and Functions via the Regulation of leg1 Transcription in the Zebrafish Embryo
- Authors
- Lin, T.Y., Chou, C.F., Chung, H.Y., Chiang, C.Y., Li, C.H., Wu, J.L., Lin, H.J., Pai, T.W., Hu, C.H., Tzou, W.S.
- ID
- ZDB-PUB-140708-1
- Date
- 2014
- Source
- PLoS One 9: e101980 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Basic Helix-Loop-Helix Transcription Factors/deficiency
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/metabolism*
- Cell Proliferation/drug effects
- Cobalt/pharmacology
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Fibroblast Growth Factors/metabolism
- Gene Expression Regulation, Developmental/drug effects
- Gene Knockdown Techniques
- Hepatocyte Growth Factor/metabolism
- Intestines/embryology
- Liver/cytology
- Liver/embryology*
- Organ Size/drug effects
- Pancreas, Exocrine/embryology
- Phenotype
- Promoter Regions, Genetic/genetics
- Response Elements/genetics
- Transcription, Genetic*
- Wnt Signaling Pathway/drug effects
- Zebrafish/embryology*
- Zebrafish/genetics*
- Zebrafish Proteins/genetics*
- PubMed
- 25000307 Full text @ PLoS One
Citation
Lin, T.Y., Chou, C.F., Chung, H.Y., Chiang, C.Y., Li, C.H., Wu, J.L., Lin, H.J., Pai, T.W., Hu, C.H., Tzou, W.S. (2014) Hypoxia-Inducible Factor 2 Alpha Is Essential for Hepatic Outgrowth and Functions via the Regulation of leg1 Transcription in the Zebrafish Embryo. PLoS One. 9:e101980.
Abstract
The liver plays a vital role in metabolism, detoxification, digestion, and the maintenance of homeostasis. During development, the vertebrate embryonic liver undergoes a series of morphogenic processes known as hepatogenesis. Hepatogenesis can be separated into three interrelated processes: endoderm specification, hepatoblast differentiation, and hepatic outgrowth. Throughout this process, signaling molecules and transcription factors initiate and regulate the coordination of cell proliferation, apoptosis, differentiation, intercellular adhesion, and cell migration. Hifs are already recognized to be essential in embryonic development, but their role in hepatogenesis remains unknown. Using the zebrafish embryo as a model organism, we report that the lack of Hif2-alpha but not Hif1-alpha blocks hepatic outgrowth. While Hif2-alpha is not involved in hepatoblast specification, this transcription factor regulates hepatocyte cell proliferation during hepatic outgrowth. Furthermore, we demonstrated that the lack of Hif2-alpha can reduce the expression of liver-enriched gene 1 (leg1), which encodes a secretory protein essential for hepatic outgrowth. Additionally, exogenous mRNA expression of leg1 can rescue the small liver phenotype of hif2-alpha morphants. We also showed that Hif2-alpha directly binds to the promoter region of leg1 to control leg1 expression. Interestingly, we discovered overrepresented, high-density Hif-binding sites in the potential upstream regulatory sequences of leg1 in teleosts but not in terrestrial mammals. We concluded that hif2-alpha is a key factor required for hepatic outgrowth and regulates leg1 expression in zebrafish embryos. We also proposed that the hif2-alpha-leg1 axis in liver development may have resulted from the adaptation of teleosts to their environment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping