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Updated: Nov 7, 2025
Hepatocyte-specific Ablation in Zebrafish to Study Biliary-driven Liver Regeneration
Published on: May 20, 2015
The Lysosomal Storage Disorder Due to fig4a Mutation Causes Robust Liver Vacuolation in Zebrafish
Wandong Bao1, Xinjuan Wang1, Lingfei Luo1
1Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China.
Abstract:
The phospholipid phosphatase FIG4/Fig4 is a subunit of PIKFYVE/Pikfyve kinase complex that synthesizes phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a key regulator of endolysosomal trafficking and function. Loss of FIG4/Fig4 leads to intracellular deficiency of PI(3,5)P2 signaling and multiple endolysosomal defects. Previous works were focused on the effects of FIG4/Fig4 mutations in the nervous and musculoskeletal systems in human clinical and animal studies. In this study, we describe a zebrafish recessive mutant cq35 showing robust liver vacuolation and lethality, with a predicted truncating mutation in fig4a gene. The liver vacuolation progress in fig4a mutant was reversible after regaining normal fig4a transcripts. The hepatic vacuolation pathology was identified as abnormal lysosomal storage with numerous accumulated cargoes, including autophagy intermediates, and caused progressive degeneration of bile canaliculi in mutant liver. These hepatic pathological details of fig4a mutant were repeated in zebrafish pikfyve mutant. Thus, zebrafish possess the conserved structural and functional mechanisms in Pikfyve kinase complex, based on which, pikfyve mutant phenotype covered fig4a mutant phenotype in their double mutant. Our findings represent the first description of the in vivo defects caused by FIG4/Fig4 mutation or PI(3,5)P2 deficiency in liver, and reveal the conserved complex mechanisms associated with FIG4/Fig4-deficient disorders in zebrafish.
Insights
Loss of FIG4/Fig4 causes liver vacuolation and lethality in zebrafish due to phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) deficiency. These defects are reversible and conserved in the Pikfyve kinase complex.
Area of Science:
- Cell Biology
- Genetics
- Zebrafish Models
Background:
- Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is crucial for endolysosomal trafficking.
- FIG4/Fig4 is a subunit of the PIKFYVE/Pikfyve kinase complex, essential for PI(3,5)P2 synthesis.
- FIG4/Fig4 mutations are linked to nervous and musculoskeletal defects.
Purpose of the Study:
- To investigate the role of FIG4/Fig4 in liver function using a zebrafish model.
- To characterize the hepatic phenotype associated with FIG4/Fig4 deficiency.
- To explore the conservation of FIG4/Fig4 function within the Pikfyve kinase complex.
Main Methods:
- Generated a zebrafish mutant (cq35) with a predicted truncating mutation in the fig4a gene.
- Analyzed liver vacuolation, lethality, and lysosomal storage in fig4a mutants.
- Compared fig4a mutant phenotypes with those of pikfyve mutants.
- Assessed reversibility of hepatic phenotype by restoring fig4a transcripts.
Main Results:
- Zebrafish fig4a mutant (cq35) exhibited severe liver vacuolation and lethality.
- Hepatic pathology involved abnormal lysosomal storage and bile canaliculi degeneration.
- The fig4a mutant phenotype was reversible upon restoration of fig4a transcripts.
- Phenotypes in fig4a mutants were recapitulated in pikfyve mutants, with pikfyve mutants covering fig4a phenotypes in double mutants.
Conclusions:
- This study provides the first in vivo description of liver defects caused by FIG4/Fig4 mutation or PI(3,5)P2 deficiency in zebrafish.
- Zebrafish fig4a mutants reveal conserved mechanisms of FIG4/Fig4 function and PI(3,5)P2 regulation in the liver.
- Findings highlight the conserved structural and functional roles of the Pikfyve kinase complex in endolysosomal homeostasis.
