2. Academic Validation
  3. Speedy A governs non-homologous XY chromosome desynapsis as a unique prerequisite for XY loop-axis organization

Speedy A governs non-homologous XY chromosome desynapsis as a unique prerequisite for XY loop-axis organization

  • EMBO J. 2025 Aug 18. doi: 10.1038/s44318-025-00528-8.
Dongteng Liu 1 2,  Yuxiang Zhang # 3,  Dongliang Li # 4 5,  Binjie Jiang # 5,  Xudong Zhao # 4 5,  Yanyan Li 4,  Zexiong Lin 4 5,  Yu Zhao 4,  Zhe Hu 5,  Shuzi Deng 4 5,  Zheng Li 3,  Haonan Lu 5,  Karen K L Chan 5,  William S B Yeung 4 5,  Philipp Kaldis 6,  Chencheng Yao 3,  Hengbin Wang 7,  Louise T Chow 8,  Kui Liu 9 10
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. ldt88@163.com.
  • 2 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. ldt88@163.com.
  • 3 Department of Andrology, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China.
  • 5 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 6 Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), Malmö, Sweden.
  • 7 Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
  • 8 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA. ltchow@uab.edu.
  • 9 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. kliugc@hku.hk.
  • 10 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. kliugc@hku.hk.
  • # Contributed equally.
PMID: 40826181 DOI: 10.1038/s44318-025-00528-8
Abstract

In mouse early pachytene spermatocytes, the X and Y chromosomes undergo rapid non-homologous (NH) synapsis and desynapsis, but the functional significance remains unknown. Here, we report that pachynema-specific knockout of Speedy A (SpdyA) from telomeres caused persistent Y-X NH synapsis, with the entire Y axis synapsed onto the X axis. This persistent Y-X NH synapsis did not interrupt meiotic sex chromosome inactivation, recombination, or sex body formation, but it disrupted X-Y loop-axis organization and homologous X-Y desynapsis, leading to spermatocyte death. Similarly, persistent Y-X NH synapsis was also observed in pachytene spermatocytes lacking TRF1, where SpdyA was frequently lost from the X-Y non-pseudoautosomal region (non-PAR) telomeres. Mechanistic studies revealed that Serine 48 of SUN1 is a key SpdyA/CDK2 phosphorylation site required for Y-X NH desynapsis. We propose that SpdyA governs Y-X NH desynapsis by stabilizing the linkage between the X-Y non-PAR telomeres and their LINC complexes, and that this process is regulated independently from Other aspects of pachynema progression. Our findings suggest a key role for Y-X NH desynapsis in establishing proper X-Y loop-axis organization.

Keywords

Mouse Pachytene Spermatocytes; Non-homologous XY Desynapsis; SpdyA; Telomeres; XY Loop-axis Organization.

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