关键词:
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
摘要:
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.