Conditional deletion of PGRMC1 disrupts spermatogenesis

Kristin Patrice Yenick

Progesterone Receptor Membrane Component 1 (PGRMC1), an X-linked gene, has been associated with cell functions including steroid metabolism, apoptosis and progression of tumorigenesis. PGRMC1 is expressed in reproductive tissues including Sertoli cells, germ cells and Leydig cells within the testes. However, the role of PGRMC1 for germ cell differentiation and steroidogenesis remains unknown. PGRMC1 is associated with the anti-apoptotic actions of progesterone in the ovarian follicle, suggesting the importance of PGRMC1 for cell survival. Based on its association with steroid metabolism and apoptosis, as well as its broad expression pattern, we hypothesized that PGRMC1 is important for the progression of germ cell differentiation and the regulation of cell survival. To test this hypothesis, we employed a Cre/loxP based approach for conditional knockout (cKO) of Pgrmc1 in male germ and somatic cells using two different cre recombinase (cre) expressing transgenic mouse lines. First, Stra8-Cre is a germ cell specific cre, which, when crossed with transgenic mice that harbor a floxed exon 2 of the Pgrmc1 gene deletes the floxed DNA. This results in conditional deletion of a functional PGRMC1 protein. Morphological evaluation of vi Stra8Cre/+ ;Pgrmc1d/Y mice demonstrated disruption of spermatogenesis, as vacuoles were present during a young developmental age. Immunohistochemistry revealed increased apoptosis and decreased proliferation within germ cells. Amhr2-Cre; drives cre recombinase expression in Sertoli and Leydig cells. Interestingly, a progressive agedependent phenotype was observed in which more than 50% of seminiferous tubules were disrupted in adult Amhr2Cre/+;Pgrmc1d/Y male mice. In addition, significantly higher serum testosterone levels were observed in Amhr2Cre/+;Pgrmc1d/Y male mice when compared with control male mice. Spermatogenesis is a dynamic and tightly regulated process, which is crucial for the development of spermatozoa. In the testis, PGRMC1 is potentially involved in steroid hormone metabolism, germ cell survival and contributes to Sertoli cell function. Our findings in combination with the actions elucidated for the female reproductive system suggests PGRMC1 acts as a governor of cell survival in somatic and germ cells of the testis. These data indicate the loss of PGRMC1 in testicular cells disrupts germ cell proliferation, Leydig cell steroidogenesis, and may lead to accelerated reproductive senescence.

Conditional deletion of PGRMC1 disrupts spermatogenesis

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