MEIOC Regulates HSPA2 to Coordinate the Timing of Early Meiosis

Shelbie Wenner^1,2; Natalie Pfaltzgraff²; Esther Ushuhuda²; Maria Mikedis^2,3

1.     Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, USA

2.     Reproductive Sciences Center, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

3.      Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA


Abstract Text:

Meiosis is a specialized process of cellular division that uniquely occurs in the gonads and produces mature gametes for reproduction. When germ cells enter meiosis, they first undergo meiotic DNA replication and then progress into prophase I, during which homologous chromosomes undergo pairing, synapsis, and recombination. These events prepare for the segregation of homologous chromosomes by the end of meiosis I, followed by the separation of sister chromatids in meiosis II. Failure to complete the chromosomal events of meiotic prophase I results in apoptosis or chromosomal missegregation at the completion of meiosis. Fertility depends on the success of meiosis, with aberrant meiosis being one of the most common causes of infertility and birth defects. However, it remains unclear how mammalian germ cells establish the cell cycle program that coordinates meiotic prophase I. In mammals, MEIOC is a germline-specific protein that contributes to the establishment of the meiotic cell cycle by repressing the mitotic cell cycle. MEIOC acts in a complex with YTHDC2 and RBM46 proteins to destabilize specific mRNA targets, including those associated with the mitotic cell cycle. When Meioc is knocked out in mouse, the germ cells are delayed in entering meiotic prophase I. Furthermore, cells progress prematurely to an abnormal metaphase, days sooner than wild-type counterparts reach meiotic metaphase I, and fail to successfully complete prophase I. The mutant metaphase has atypical features such as disorganized, unipolar spindles. It is unknown if this metaphase is a continuation of the mitotic cell cycle or an advancement of the meiotic one. We discovered that MEIOC represses HSPA2, a protein required for progression from late prophase I to metaphase I during spermatogenesis. In wild-type spermatogenic cells, HSPA2 is first detected during late prophase I. In Meioc knockout cells, HSPA2 is prematurely expressed in early prophase I. Here, we test the hypothesis that MEIOC’s regulation of HSPA2 protein expression impacts the timing of meiotic prophase I and metaphase. In ongoing and future experiments, we use a genetic approach to molecularly dissect how spermatogenic cells’ progression through meiotic prophase I is regulated by MEIOC and HSPA2. Our studies will molecularly define how MEIOC regulates HSPA2 to determine the timing of meiotic prophase I. This will expand our molecular understanding of the regulation of key events in the meiotic cell cycle and may provide novel opportunities to facilitate in vitrospermatogenesis, a potential regenerative medicine-based treatment for infertility.