Hyperactivated Wnt-β-catenin signaling in the absence of sFRP1 and sFRP5 disrupts trophoblast differentiation through repression of Ascl2

BMC Biology

Yongqin Yu¹  Change Mu¹  Chunping Wang¹  Yingchun Xu¹  Dong Liu¹  Qian Han¹  Sanmei Liu¹  Yang Sun¹  Fan Liu¹  Haibin Wang²  Wenbo Deng²  Shuangbo Kong²  Bin Cao²  Han Cai²  Jinhua Lu²  Haili Bao³  Qiang Wang⁴ 

[1] Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102, Xiamen, Fujian, People’s Republic of China;Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, People’s Republic of China;Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102, Xiamen, Fujian, People’s Republic of China;Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, People’s Republic of China;Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102, Xiamen, Fujian, People’s Republic of China;State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, People’s Republic of China;State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, People’s Republic of China;Department of Surgery, The Ohio State University Wexner Medical Center, 43210, Columbus, Ohio, USA;

关键词: Sfrp1;    Hyperactivation;    Canonical Wnt pathway;    Trophoblast;    Ascl2;   

DOI  :  10.1186/s12915-020-00883-4

来源: Springer

【 摘 要 】

BackgroundWnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development.ResultsIn the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression.ConclusionsOur investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.

【 授权许可】

CC BY