Related Experiment Video
Updated: May 6, 2026
Hepatocyte-specific Ablation in Zebrafish to Study Biliary-driven Liver Regeneration
Published on: May 20, 2015
Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene
Shuang Cui1, Melissa Leyva-Vega, Ellen A Tsai
1Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Insights
Glypican 1 (GPC1) deletions are linked to biliary atresia (BA) in infants. Studies in zebrafish show GPC1 is crucial for biliary development and suggest Hedgehog signaling plays a role in BA.
Area of Science:
- Genetics
- Developmental Biology
- Pediatric Gastroenterology
Background:
- Biliary atresia (BA) is a neonatal liver disorder with unknown causes, potentially involving genetic susceptibility and environmental factors.
- The 2q37 chromosomal region has been implicated in BA susceptibility.
- Identifying specific genes involved in hepatobiliary development is crucial for understanding BA pathogenesis.
Purpose of the Study:
- To narrow down the 2q37 region and identify specific genes associated with biliary atresia susceptibility.
- To investigate the role of candidate genes in biliary development and signaling pathways.
Main Methods:
- Comparative genomic analysis to identify copy number variants in BA patients versus controls.
- Zebrafish model to study gene function, expression patterns, and developmental effects of gene knockdown.
- Investigated the impact of Hedgehog pathway modulation on biliary development.
Main Results:
- Increased deletions at 2q37.3, specifically involving the GPC1 gene, were observed in BA patients.
- GPC1 encodes glypican 1, a regulator of Hedgehog signaling and inflammation.
- Knockdown of GPC1 in zebrafish caused biliary developmental defects, partially rescued by Hedgehog pathway modulation. BA patient liver samples showed reduced GPC1 levels.
Conclusions:
- Glypican 1 (GPC1) is identified as a susceptibility gene for biliary atresia.
- Hedgehog signaling pathway is implicated in the pathogenesis of biliary atresia.
Background & Aims:
Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes.
Methods:
We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction.
Results:
We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls.
Conclusions:
Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA.
