Cdx1b protects intestinal cell fate by repressing signaling networks for liver specification

Qingxia Jin; Yuqi Gao; Shimin Shuai; Yayue Chen; Kaiyuan Wang; Jun Chen; Jinrong Peng; Ce Gao

doi:10.1016/j.jgg.2022.11.006

Volume 49 Issue 12

Dec. 2022

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Cdx1b protects intestinal cell fate by repressing signaling networks for liver specification

doi: 10.1016/j.jgg.2022.11.006

a. College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China;
b. Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China;
c. College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China

Funds:

31830113).

The authors are grateful to Xiangfeng Shen (for maintaining the fish facility) and Jian Hong (for TEM analysis) for their technical support with animal studies. We specifically thank Professor Bo Zhang for sharing the prox1a gene-specific gRNA information. S.M.S and N.X. are supported by Centre for Computational Science and Engineering (CCSE) at Southern University of Science and Technology. This work is supported by the National Key R&D Program of China (2018YFA0800502), and the National Natural Science Foundation of China (31900579

Received Date: 2022-11-08
Accepted Date: 2022-11-21
Rev Recd Date: 2022-11-20
Publish Date: 2022-11-29

Abstract

Abstract

In mammals, the expression of the homeobox family member Cdx2/CDX2 is restricted within the intestine. Conditional ablation of the mouse Cdx2 in the endodermal cells causes a homeotic transformation of the intestine towards the esophagus or gastric fate. In this report, we show that null mutants of zebrafish cdx1b, encoding the counterpart of mammalian CDX2, could survive more than 10 days post fertilization, a stage when the zebrafish digestive system has been well developed. Through RNA sequencing (RNA-seq) and single-cell sequencing (scRNA-seq) of the dissected intestine from the mutant embryos, we demonstrate that the loss-of-function of the zebrafish cdx1b yields hepatocyte-like intestinal cells, a phenotype never observed in the mouse model. Further RNA-seq data analysis, and genetic double mutants and signaling inhibitor studies reveal that Cdx1b functions to guard the intestinal fate by repressing, directly or indirectly, a range of transcriptional factors and signaling pathways for liver specification. Finally, we demonstrate that heat shock-induced overexpression of cdx1b in a transgenic fish abolishes the liver formation. Therefore, we demonstrate that Cdx1b is a key repressor of hepatic fate during the intestine specification in zebrafish.
- Cdx1b,
- CDX2,
- Hhex,
- Intestine development,
- Liver development,
- Prox1a,
- Zebrafish

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References(55)

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