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Glucocorticoid Receptor Signaling in the Mammalian Germline

Abstract

While physiologic stress has long been known to impair mammalian reproductive capacity through hormonal dysregulation, mounting evidence now suggests that stress experienced prior to or during gestation may also negatively impact the health of future offspring. A growing body of work in recent years has clearly demonstrated that rodent models of physiologic stress can induce a variety of neurologic and behavioral phenotypes that are able to persist for up to three generations, suggesting that stress signals can induce lasting epigenetic changes in the germline. Any perturbations to the proper transmission of genetic information through the germ cells can be detrimental, and thus understanding the mechanism by which stress can lead to epigenetic alterations in the germline remains a crucial unanswered question in the field. Interestingly, treatment with glucocorticoid stress hormones is sufficient to recapitulate the transgenerational phenotypic inheritance seen in physiologic stress models. These hormones are known to bind and activate the glucocorticoid receptor (GR), a ligand-inducible transcription factor, thus implicating GR-mediated signaling as a potential contributor to the transgenerational inheritance of stress-induced phenotypes. It remains unclear, however, whether the heritability of stress-induced phenotypes following glucocorticoid treatment results from direct actions of glucocorticoids on the germ cells of the gonad, or from indirect effects of glucocorticoids elsewhere in the body. Moreover, evidence for the expression of GR in the developing and adult germ cells of both the male and female remains controversial, making it difficult to assess any potential cell-autonomous roles of GR in modulating the epigenome of the germline in response to stress. We therefore set out to definitively characterize the expression of GR in the germline of the developing and adult gonads, and to determine what cell-intrinsic role GR plays in normal germline formation and function. We discovered that GR is expressed in the female germline specifically during fetal development (peaking at approximately E13.5 - E14.5), yet is absent from the adult oocyte. We found that the female germline is, surprisingly, resistant to changes in GR signaling. Both genetic deletion of GR as well as GR agonism with dexamethasone revealed minimal transcriptional changes in the female germ cells, as well as no significant changes in meiotic progression, suggesting the female germline is intrinsically buffered against changes in GR signaling. In contrast we found that GR is expressed in the male germline during the final days of development, with expression maintained in pro-spermatogonia during early postnatal development. This expression becomes restricted to the spermatogonia of the adult, and transcriptomic analysis of germ cells from dexamethasone treated males revealed a potential role of GR in regulating RNA splicing. Together our data confirm the dynamic spatiotemporal expression of GR in both the male and female germ cells of the mouse, and suggest a sexually dimorphic function for this receptor in the mammalian germline.

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