Oestrogen regulates SOX9 bioavailability by rapidly activating ERK1/2 and stabilising microtubules in a human testis-derived cell line

Oestrogen Activates the MAP3K1 Cascade and β-Catenin to Promote Granulosa-like Cell Fate in a Human Testis-Derived Cell Line

“…The downstream targets of MAP3K1—MAP2K1 and MAP2K2—increased in abundance after 48 h; however, only MAP2K2 was significant. We also observed an increase in the phosphorylation of MAPK1 (ERK2) at Tyr187 (a site that leads to activation) after 30 min, consistent with our previous findings showing that EE2 activated ERK1/2 in NT2/D1 cells [ 25 ]. This was statistically non-significant ( p = 0.106), although all replicates showed a consistent trend with increasing abundance (raw values for each replicate were log 2 FC 0.95, 0.80, 0.55 and 3.11).…”

“…We have previously demonstrated that exposure to oestrogen can cause the cytoplasmic retention of SOX9 in testis cells, leading to a decrease in expression of genes that drive male development and increased expression of pro-ovarian genes [ 23 , 24 ]. We showed that oestrogen treatment rapidly activated ERK1/2 to promote microtubule stabilisation, resulting in the cytoplasmic retention of SOX9 [ 25 ]. The MAP3K1/3K4 cascades can activate ERK1/2 and cause a shift from pro-testis (SOX9) to pro-ovarian (β-catenin) activity in the gonads.…”

“…We previously demonstrated that oestrogen causes cytoplasmic retention of SOX9 via non-genomic signalling cascades that rapidly activate ERK1/2 (a member of the mitogen activated protein kinase (MAPK) family) and promote the stabilisation of microtubules [ 25 ]. ERK1/2 is known to be oestrogen responsive across a broad range of cell types [ 26 , 27 , 28 , 29 ] and its activation is also observed in MAP3K1 gain-of-function mutations that are associated with XY gonadal dysgenesis in humans [ 30 , 31 ].…”

Exogenous Oestrogen Impacts Cell Fate Decision in the Developing Gonads: A Potential Cause of Declining Human Reproductive Health

“…ERK1/2 can be activated by oestrogen in a non-genomic manner in breast cancer, bone, and neural cells [157][158][159][160]. Brief oestrogen treatment can also rapidly activate ERK1/2 in NT2/D1 cells to promote the cytoplasmic retention of SOX9 [161], demonstrating oestrogen can mediate SOX9 on both a non-genomic and genomic level. These results suggest oestrogen activates ERK1/2 in Sertoli cells to promote ovarian fate through stabilisation of β-catenin and inhibition of SOX9 (Figure 3).…”

“…Altogether, the activation of ERK1/2, AKT, PKA, and PAK1 present as potential targets of oestrogen to promote ovarian fate in Sertoli cells (Figure 3); however, it is difficult to predict how these kinases may respond in a different cell type and what impacts their activation would have on other aspects of the cell. The findings that oestrogen can rapidly activate ERK1/2 to suppress SOX9 [161] demonstrates how essential assessing the effects of oestrogen on non-genomic targets is, as this type of signalling often establishes the changes required for genomic signalling to occur. Furthermore, these signalling pathways are critical for spermatogenesis and have been linked to male infertility [180], further supporting the impacts of exogenous oestrogen on non-genomic pathways and declining male reproductive health.…”