Prox1a promotes liver growth and differentiation by repressing <i>cdx1b</i> expression and intestinal fate transition in zebrafish

Yingying Hu; Zhou Luo; Meiwen Wang; Zekai Wu; Yunxing Liu; Zhenchao Cheng; Yuhan Sun; Jing-Wei Xiong; Xiangjun Tong; Zuoyan Zhu; Bo Zhang

doi:10.1016/j.jgg.2024.09.010

Volume 52 Issue 1

Jan. 2025

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Prox1a promotes liver growth and differentiation by repressing cdx1b expression and intestinal fate transition in zebrafish

doi: 10.1016/j.jgg.2024.09.010

a. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China;
b. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen University Town, Shenzhen, Guangdong 518055, China;
c. College of Biological Sciences, China Agricultural University, Beijing 100193, China;
d. Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China

Funds:

We thank Yingdi Jia, Jingliang Chen, Yuying Gao, and Yan Shen for maintaining the zebrafish, fish facilities, and laboratory equipment. We thank Xiaoying Fan in Professor Fuchou Tang's lab for technical assistance with the preparation of microscale RNA libraries. We thank Professor Michel Bagnat for providing the TgBAC(cldn15la-GFP) fish line, the China Zebrafish Resource Center and Zhiyuan Gong lab for providing the Tg(fabp10a:DsRed) fish line, and the Laboratory Animal Center, Institute of Molecular Medicine, Peking University, for assistance with HE staining. We thank Xuemei Hao and all other members of the Core Facilities at the Peking University School of Life Sciences and the National Center for Protein Sciences at Peking University in Beijing, China, for assistance with imaging. This work was partially supported by grants from the National Key Research and Development Program of China and the National Natural Science Foundation of China (2018YFA0801000, 32270889, 2019YFA0802800, 32070824, 2015CB942800, 2016YFA0100500, 31871458, 31671500, and 81371264). This work was also supported by Beijing Natural Science Foundation (5242009), as well as a grant from the Fisheries Innovation Team of Beijing Agriculture Innovation Consortium (BAIC07-2023-02).

Received Date: 2024-09-01
Accepted Date: 2024-09-19
Rev Recd Date: 2024-09-14

Available Online: 2025-07-11

Publish Date: 2024-09-27

Abstract

Abstract

The liver is a key endoderm-derived multifunctional organ within the digestive system. Prospero homeobox 1 (Prox1) is an essential transcription factor for liver development, but its specific function is not well understood. Here, we show that hepatic development, including the formation of intrahepatic biliary and vascular networks, is severely disrupted in prox1a mutant zebrafish. We find that Prox1a is essential for liver growth and proper differentiation but not required for early hepatic cell fate specification. Intriguingly, prox1a depletion leads to ectopic initiation of a Cdx1b-mediated intestinal program and the formation of intestinal lumen-like structures within the liver. Morpholino knockdown of cdx1b alleviates liver defects in the prox1a mutant zebrafish. Finally, chromatin immunoprecipitation analysis reveals that Prox1a binds directly to the promoter region of cdx1b, thereby repressing its expression. Overall, our findings indicate that Prox1a is required to promote and protect hepatic development by repression of Cdx1b-mediated intestinal cell fate in zebrafish.
- Zebrafish,
- Liver development,
- prox1a,
- cdx1b,
- Cell fate transition

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References(73)

References

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