An animal model recapitulates human hepatic diseases associated with <i>GATA6</i> mutations
Abstract
Heterozygotic GATA6 mutations are responsible for various congenital diseases in the heart, pancreas, liver, and other organs in humans. However, there is lack of an animal that can comprehensively model these diseases since GATA6 is essential for early embryogenesis. Here, we report the establishment of a gata6 knockout zebrafish which recapitulates most of the symptoms in patients with GATA6 mutations, including cardiac outflow tract defects, pancreatic hypoplasia/agenesis, gallbladder agenesis, and various liver diseases. Particularly in the liver, the zebrafish gata6 model exhibits the paucity of intrahepatic bile ducts, disrupted bile canaliculi, cholestasis, resembling the liver diseases associated with GATA6 mutations. Moreover, an unreported phenotype, hepatic cysts, has been also revealed in the model. Mechanistically, Gata6 interacts with Hhex and binds lrh-1 promoter to synergistically activate its expression, thereby enhancing the Lrh-1-mediated β-catenin signaling which is essential for liver development. This transcriptional activation of lrh-1 is tightly controlled by the negative feedback, in which Lrh1 interacts with Gata6 to weaken its transactivation ability. Moreover, Gata6 level is regulated by Hhex-mediated proteasomal degradation. The orchestration by these three transcription factors precisely modulates Gata6 activity, ensuring β-catenin signaling output and proper liver development in zebrafish. Importantly, the molecular mechanism identified in zebrafish is conserved in human cells. GATA6 mutant variants associated with hepatobiliary malformations in humans interact aberrantly with HHEX, resulting in subsequent impairments of LRH-1 activation. Conclusively, the disease model established here provides both phenotypic and mechanism insights into the human hepatic diseases associated with GATA6 mutations.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Wenpeng Shi
Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University
Xiaogui Yi
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Hua Ruan
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Donglei Wang
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Dan Wu
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Pengfei Jiang
School of Life Sciences, The National Engineering Laboratory of Crop Resistance Breeding, Anhui Agricultural University
Lisha Luo
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Xirui Ma
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Faming Jiang
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Cairui Li
Dali Bai Autonomous Prefecture People’s Hospital, The Third Affiliated Hospital of Dali University
Weinan Wu
Affiliated Hospital of Guangdong Medical University and Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University
Lingfei Luo
Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University
Li Li
Guixue Wang
Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University
Juhui Qiu
Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University
Honghui Huang
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University