PTBP1 supports mouse spermatogenesis by facilitating cytoskeletal organization through the mTORC2–PKCα pathway in Sertoli cells

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Abstract
Somatic Sertoli cells in the seminiferous tubule provide structural and paracrine support for spermatogenesis. Proper regulation of Sertoli cell cytoskeleton dynamics is essential for this function; however, the regulatory mechanisms remain unclear. Here, we found that polypyrimidine tract-binding protein 1 (PTBP1) maintained cytoskeletal integrity in Sertoli cells via mTORC2 signaling. Sertoli cell–specific Ptbp1 deletion in mice resulted in germ cell loss, blood–testis barrier disruption, and male infertility. Transcriptomic analysis of purified Sertoli cells revealed the dysregulation of cytoskeletal and adhesion-related genes. RNA immunoprecipitation sequencing demonstrated that PTBP1 bound to Rictor mRNA. PTBP1 loss reduced RICTOR protein expression and downstream PKCα activation, impairing the F-actin cytoskeleton. Cytoskeletal defects caused by PTBP1 deficiency were restored by constitutively active PKCα, confirming the functional relevance of the mTORC2–PKCα axis. These findings highlighted PTBP1’s role as a post-transcriptional regulator of male fertility through the maintenance of Sertoli cell architecture and spermatogenesis.
Funding Information
  • MEXT | Japan Society for the Promotion of Science (JP21H05033)
  • MEXT | Japan Society for the Promotion of Science (20H03162)
  • MEXT | Japan Society for the Promotion of Science (23H02391)
  • MEXT | JST | Core Research for Evolutional Science and Technology (JPMJCR21N1)
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088412)
  • Bill and Melinda Gates Foundation (INV-001902)

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