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    • In this study we examined the impact of

    2018-10-24

    In this study, we examined the impact of hormonal signaling on SSC self-renewal using follicle-stimulating hormone β (Fshb; FSH β subunit) and luteinizing hormone/choriogonadotropin receptor (Lhcgr) KO mice. FSH acts on Sertoli estrogen related receptor within seminiferous tubules, while LHCGR are detected only on the testosterone-producing Leydig cells located between the tubules. Fshb KO mice are fertile but have smaller testes with reduced Sertoli and germ cell numbers (Kumar et al., 1997). Lhcgr KO mice have undescended testes and are infertile (Lei et al., 2001; Zhang et al., 2001). SSC activities of immature and mature testes of these mutant mice were determined based on spermatogonial transplantation into WT mice. We also examined the effect of mutant testicular microenvironments on SSC homing and self-renewal division by serial transplantation. Microarray analysis revealed that Wnt5a is involved in SSC self-renewal by hormonal signaling.
    Results
    Discussion Regulation of SSC self-renewal by gonadotropic hormones has been suggested since the early days of spermatogonial transplantation experiments. Several studies based on GnRH analog administration have demonstrated the involvement of the gonadotropic pituitary hormone in SSC regulation (Dobrinski et al., 2001; Ogawa et al., 1998), which was confirmed by another study using hypophysectomized animals (Kanatsu-Shinohara et al., 2004). However, the mechanism underlying this phenomenon has remained unclear. Moreover, controversy exists regarding the regulation of GDNF expression (Chen and Liu, 2016). In this study, we explored this question using Fshb and Lhcgr KO mice and dissected the role of gonadotropic pituitary hormones in SSC regulation. Analysis of Fshb KO mice showed that SSCs in these animals are apparently normal. Immunohistochemical staining indicated that the numbers of GFRA1+ spermatogonia and undifferentiated spermatogonia were not significantly different from those in WT mice. Because a positive relationship between FSH receptor and GDNF expression was reported (Ding et al., 2011; Tadokoro et al., 2002), we expected that SSCs would be significantly reduced in Fshb KO mice. However, Fshb KO mice contained a normal number of SSCs, suggesting that the lack of FSH signaling does not influence SSCs. These results were in contrast to previous studies that showed the beneficial effects of FSH on GDNF expression (Ding et al., 2011; Tadokoro et al., 2002). At least two explanations may explain this difference. The first is the method of FSH suppression. Although GnRH treatment was shown to increase GDNF expression in vivo via FSH suppression (Tadokoro et al., 2002), this treatment also decreases LH levels, which were not investigated in the previous report because of the lack of effect of testosterone on GDNF expression in vitro. The second is the experimental method; several studies showing increased GDNF expression were based on testis cell culture. However, FSH receptor expression levels may have changed by dissociation into single cells, and the continuous exposure to high levels of FSH in vitro may not have reflected physiological regulation of GDNF. Transplantation of Lhcgr KO mouse testis resulted in enhanced colonization of adult donor cells. Lhcgr KO mice are characterized by immature Leydig cells and lack of Leydig stem cells (Lei et al., 2001; Lo et al., 2004). Leydig cells in Lhcgr KO mice are of the fetal type and the concentration of testosterone is very low (Zhang et al., 2001). Because it has been suggested that Leydig cells contribute to SSC niches and a recent study showed positive regulation of GDNF by testosterone (Chen et al., 2014; Oatley et al., 2009), we expected that SSCs in these mice might be decreased due to the lack of adult-type Leydig cells. However, we found an increased number not only of GFRA1-expressing spermatogonia but also SSCs. While these results suggest that SSC activity is not compromised by the lack of mature Leydig cells or testosterone, it remains possible that the enrichment of SSCs was due to the absence of differentiating germ cells.