Abstract
Spermatogonia stem cell (SSC) self-renewal and differentiation are tightly regulated processes that ensure a continued production of mature sperm throughout male adulthood. In the present study, we investigated the role of glucocorticoid-induced leucine zipper (GILZ) in maintenance of the male germline and spermatogenesis. GILZ was detectable in germ cells of wild type mice on the day of birth, suggesting a role for GILZ in prospermatogonia and SSC pool formation. Gilz KO mice were generated and adult males were azoospermic and sterile. During the first wave of spermatogenesis in Gilz KO mice, spermatogenesis arrested part way through pachytene of meiosis I. Subsequent waves resulted in a progressive depletion of germ cells through apoptosis to ultimately produce a Sertoli cell-only phenotype. Further, in contrast to wild type littermates, PLZF+ cells were detected in the peri-luminal region of Gilz KO mice at day 6 post-natal, suggesting a defect in prospermatogonia migration in the absence of GILZ. At age 30 days, transient accumulation of PLZF+ cells in a subset of tubules and severely compromised spermatogenesis were observed in Gilz KO mice, consistent with defective SSC differentiation. GILZ deficiency was associated with an increase in FOXO1 transcriptional activity, which leads to activation of a selective set of FOXO1 target genes, including a pro-apoptotic protein, BIM. On the other hand, no evidence of a heightened immune response was observed. Together, these results suggest that GILZ suppresses FOXO1 nuclear translocation, promotes SSC differentiation over self-renewal, and favours germ cell survival through inhibition of BIM-dependent pro-apoptotic signals. These findings provide a mechanism for the effects of GILZ on spermatogenesis and strengthen the case for GILZ being a critical molecule in the regulation of male fertility.
Highlights
The two main functions of spermatogonial stem cells (SSC) are to maintain the SSC population through self-renewal and to generate differentiating daughter spermatogonia for spermatogenesis [1,2]
To define in more detail, the expression of Glucocorticoid-induced leucine zipper (GILZ) mRNA levels were measured by quantitative PCR on testis samples taken at key points during the establishment of the first spermatogenic cycle in WT mice
GILZ was first identified as a glucocorticoid-induced protein, and its functions as a transducer of anti-inflammatory signals have been reported in a wide range of cells during the past 15 years
Summary
The two main functions of spermatogonial stem cells (SSC) are to maintain the SSC population through self-renewal and to generate differentiating daughter spermatogonia for spermatogenesis [1,2]. The molecular mechanisms underlying the transition of SSCs from self-renewal towards differentiation remain poorly understood, a recent study suggested that Forkhead box O (FOXO) proteins play an important role [3]. Goertz et al reported that either deletion or hyperactivation of FOXO1 can lead to spermatogenic failure, suggesting that very tight control of FOXO1 activity is required to maintain the balance between SSC self-renewal and differentiation. The majority of GILZ-related research has focused on its anti-inflammatory effects, a role of GILZ in the regulation of cell differentiation [7] and cell death [8] has been reported. Given the importance of FOXO proteins in fertility, and a recent report demonstrating GILZ expression during early stages of spermatogenesis [11], we hypothesized that GILZ might impact on fertility via effects on FOXO proteins
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