Progesterone receptor membrane components 1 and 2 are required for spermatogenesis and male fertility

Alanna Chloe Grossman

doi:10.7273/000004292

Progesterone receptor membrane component (PGRMC) 1 and 2 are non-classical progesterone (P4) receptors with both P4-dependent and P4-independent mechanisms. These proteins have ubiquitous expression patterns and are well-studied in the female reproductive tract, having been shown to be essential for female fertility and maintenance of early pregnancy. Despite the breadth of information on PGRMC1/2 in the female, currently there is virtually nothing known about the function of these proteins during male gametogenesis. As such, it is hypothesized that PGRMC1/2 are essential for male fertility. To test this hypothesis, Pgrmc1 and/or Pgrmc2 (Pgrmc1fl/Y, Pgrmc2fl/fl, or Pgrmc1/2fl/fl) floxed mice were crossed with Stra8-cre mice for conditional ablation of PGRMC family members from the male germline (i.e., Pgrmc1d/Y, Pgrmc2d/d, or Pgrmc1/2d/d mice). Breeding trial data revealed a strong phenotype, with 60% of Pgrmc1/2d/d mice being completely infertile and 40% of Pgrmc1/2d/d mice exhibiting subfertility that progressed to complete infertility by 6-9 months of age. Computer-assisted sperm analysis showed no significant decrease in sperm parameters of Pgrmc1d/Y or Pgrmc2d/d sperm, however Pgrmc1/2d/d mice exhibited a 70% reduction in sperm concentration (p=0.008) with less than 30% of those sperm being progressively motile. A histological evaluation pinpointed two potential phenotypes in the Pgrmc1/2d/d testis. First, vacuolated spaces were evident along the basement membrane, indicative of apoptosis. This was confirmed by TUNEL staining. There was a tendency toward an increase in the number of STRA8 positive tubules that paralleled a significant increase in the number of tubules containing mitotic immature spermatogonia. Morphologically abnormal and round germ cells were present in the seminiferous tubules and the epididymal lumen, a feature indicative of failure to complete meiosis or initiate spermatid elongation. Consistent with this phenotype was the increased number of meiotic stage XII tubules. Given the known functions of PGRMCs and the observation of spermatogenic issues occurring around the time of mitosis and meiosis, it is possible that they play a role in microtubule spindle assembly/function, messenger RNA processing, trafficking, or translation, or in the metabolism and transport of heme. Overall, these studies offer the first in vivo insights into the functional requirement of PGRMC proteins in male gametogenesis.

Progesterone receptor membrane components 1 and 2 are required for spermatogenesis and male fertility

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