MON-LB130 Glucocorticoid Receptor Signaling and Stress in the Developing Mammalian Germline

While the consequences of stress on organs such as the heart and immune system have long been established, it has only recently been shown in mice that stress experienced during pregnancy can cause molecular and behavioral changes in the exposed fetus, and even their offspring. The transmission of such phenotypes across generations implies that fetal germ cells can sense and maintain epigenetic memories of stress experienced in the womb. However, how the fetal germ cells within the developing embryo detect and respond to these stress signals is unknown. In response to stress, the major circulating hormone released is cortisol, which is the ligand for the nuclear hormone receptor known as the glucocorticoid receptor (GR). GR induces highly cell type-specific transcriptional changes in many cell types, although its function in germ cells has yet to be explored. Our preliminary studies have shown, for the first time, the robust expression and dynamic localization of GR in fetal germ cells, suggesting its activity during a crucial window of epigenetic reprogramming in male and female germ cell development. Fetal germ cells naturally undergo genome-wide demethylation of somatic and parental imprints, which leads to the de-repression of transposons that are normally silenced by methylation at their promoters. If not properly re-silenced, these transposons will generate large numbers of DNA double strand breaks during transposition, posing a serious risk to germline integrity. When GR was genetically deleted from all cells of the mouse body, we discovered elevated expression of the retrotransposon, Line1 (L1), specifically in the developing germ cells. Surprisingly, mice with a conditional deletion of GR specifically in germ cells were unable to phenocopy the full body knockout, implying that GR-mediated repression of L1 in fetal germ cells is a non-cell autonomous effect. Rather, conditional deletion of GR from the surrounding somatic cells (e.g. granulosa cells of the ovary) demonstrated increased germ cell L1 expression, strongly suggesting that GR signaling through the somatic niche is indirectly regulating L1 expression in neighboring germ cells. We therefore hypothesize that GR signaling from the somatic cell niche is functioning to indirectly suppress L1 expression within the developing fetal germ cells, which holds broad implications for how stress signals mediated by GR signaling can influence germline integrity and thus the health of future generations.