LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs

Author:

Kang Jun-Yan1ORCID,Wen Ze1,Pan Duo1,Zhang Yuhan2ORCID,Li Qing1ORCID,Zhong Ai1,Yu Xinghai34ORCID,Wu Yi-Chen1,Chen Yu5,Zhang Xiangzheng5,Kou Peng-Cheng1,Geng Junlan1,Wang Ying-Yi1,Hua Min-Min16,Zong Ruiting7ORCID,Li Biao8ORCID,Shi Hui-Juan6,Li Dangsheng1ORCID,Fu Xiang-Dong9,Li Jinsong11011ORCID,Nelson David L.7ORCID,Guo Xuejiang5ORCID,Zhou Yu34ORCID,Gou Lan-Tao1ORCID,Huang Ying2ORCID,Liu Mo-Fang11011ORCID

Affiliation:

1. State Key Laboratory of Molecular Biology, State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

2. Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai Research Center of Biliary Tract Disease, Department of General Surgery, Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.

3. State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.

4. Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.

5. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

6. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Pharmacy School, Fudan University, Shanghai, China.

7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

8. Department of Nuclear Medicine, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.

9. Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA.

10. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.

11. School of Life Science and Technology, Shanghai Tech University, Shanghai, China.

Abstract

Postmeiotic spermatids use a unique strategy to coordinate gene expression with morphological transformation, in which transcription and translation take place at separate developmental stages, but how mRNAs stored as translationally inert messenger ribonucleoproteins in developing spermatids become activated remains largely unknown. Here, we report that the RNA binding protein FXR1, a member of the fragile X–related (FXR) family, is highly expressed in late spermatids and undergoes liquid-liquid phase separation (LLPS) to merge messenger ribonucleoprotein granules with the translation machinery to convert stored mRNAs into a translationally activated state. Germline-specific Fxr1 ablation in mice impaired the translation of target mRNAs and caused defective spermatid development and male infertility, and a phase separation–deficient FXR1 L351P mutation in Fxr1 knock-in mice produced the same developmental defect. These findings uncover a mechanism for translational reprogramming with LLPS as a key driver in spermiogenesis.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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