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MAST4 controls cell cycle in spermatogonial stem cells.

Seung-Jun Lee1, Ka-Hwa Kim1, Dong-Joon Lee1

  • 1Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, South Korea.

Cell Proliferation
|January 2, 2023
PubMed
Summary

Microtubule-associated serine/threonine kinase 4 (MAST4) is crucial for male fertility. MAST4 in Sertoli cells regulates spermatogonial stem cell (SSC) self-renewal by controlling cell cycle progression via CDK2-PLZF interaction.

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Area of Science:

  • Reproductive Biology
  • Cell Biology
  • Molecular Endocrinology

Background:

  • Spermatogonial stem cell (SSC) self-renewal is vital for male fertility and relies on intricate signaling between Sertoli cells and SSCs.
  • Microtubule-associated serine/threonine kinase 4 (MAST4) was previously identified as a regulator of SSC self-renewal within Sertoli cells.

Purpose of the Study:

  • To elucidate the signaling mechanism by which MAST4 in Sertoli cells regulates SSCs, with a specific focus on cell cycle control.
  • To investigate the role of the MAST4 pathway in maintaining SSC self-renewal and spermatogenesis.

Main Methods:

  • Examined PLZF, CDK2, and PLZF target gene expression in wild-type (WT) and Mast4 knockout (KO) testes using immunohistochemistry, RT-qPCR, and western blot.
  • Analyzed SSC cell cycle progression in WT and Mast4 KO mice following IdU and BrdU injections.
  • Utilized in vitro testis tissue culture to assess MAST4 pathway regulation of the cell cycle.

Main Results:

  • Mast4 KO mice exhibited infertility, Sertoli cell-only syndrome, and reduced sperm counts.
  • MAST4 deletion resulted in decreased PLZF expression and impaired cell cycle progression in testicular cells.
  • MAST4 promotes CDK2-mediated phosphorylation of PLZF, which activates PLZF to suppress cell cycle arrest genes, maintaining the SSC state.

Conclusions:

  • MAST4 is essential for maintaining SSC cell cycle progression and self-renewal through the CDK2-PLZF signaling axis.
  • The MAST4 pathway plays a pivotal role in regulating SSCs and is significant for successful spermatogenesis.
  • Dysregulation of MAST4 impacts male fertility, highlighting its therapeutic potential.