RNA-binding proteins DND1 and NANOS3 cooperatively suppress the entry of germ cell lineage

Ziqi Wang, Honglin Yu, Zhaoyu Gu, Xiaohui Shi, Jiayue Ma, Qizhe Shao, Yao Yao, Shuo Yao, Yan Xu, Yashi Gu, Jiayue Dai, Qi Liu, Jingyan Shi, Rujie Qi, Yue Jin, Yuqian Liu, Xinchen Shen, Wenwen Huang, Heng-Jia Liu, Min Jin, Wanlu Liu, Matthew Brook () and Di Chen ()
Additional contact information
Ziqi Wang: Zhejiang University
Honglin Yu: Zhejiang University
Zhaoyu Gu: Zhejiang University
Xiaohui Shi: Zhejiang University
Jiayue Ma: Zhejiang University
Qizhe Shao: Zhejiang University
Yao Yao: Zhejiang University
Shuo Yao: Zhejiang University
Yan Xu: Zhejiang University
Yashi Gu: Zhejiang University
Jiayue Dai: Zhejiang University
Qi Liu: Zhejiang University
Jingyan Shi: Zhejiang University
Rujie Qi: Zhejiang University
Yue Jin: The University of Edinburgh
Yuqian Liu: The University of Edinburgh
Xinchen Shen: Zhejiang University
Wenwen Huang: Zhejiang University
Heng-Jia Liu: The University of Edinburgh
Min Jin: Zhejiang University
Wanlu Liu: Zhejiang University
Matthew Brook: Queen’s Medical Research Institute, University of Edinburgh
Di Chen: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Specification of primordial germ cells (PGCs) establishes germline development during early embryogenesis, yet the underlying mechanisms in humans remain largely unknown. Here, we reveal the functional roles of germline-specific RNA-binding protein (RBP) DND1 in human PGC (hPGC) specification. We discovered that DND1 forms a complex with another RBP, NANOS3, to restrict hPGC specification. Furthermore, by analyzing the mRNAs bound by DND1 and NANOS3, we found that DND1 facilitates the binding of NANOS3 to hPGC-like cells-related mRNAs. We identified SOX4 mRNAs as the key downstream factor for the DND1 and NANOS3 complex. Mechanistically, DND1 and NANOS3 function in processing bodies (P-bodies) to repress the translation of SOX4 mRNAs, with NANOS3 mediating the interaction between DND1 and the translational repressor 4E-T. Altogether, these findings identify the RBP complex formed by DND1 and NANOS3 functioning as a “braking system” to restrict the entry of germ cell fate in humans.

Date: 2025
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DOI: 10.1038/s41467-025-57490-6

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