Retinoic acid-stimulated ERK1/2 pathway regulates meiotic initiation in cultured fetal germ cells

Abstract

In murine fetal germ cells, retinoic acid (RA) is an extrinsic cue for meiotic initiation that stimulates transcriptional activation of the Stimulated by retinoic acid gene 8 (Stra8), which is required for entry of germ cells into meiotic prophase I. Canonically, the biological activities of RA are mediated by nuclear RA receptors. Recent studies in somatic cells found that RA noncanonically stimulates intracellular signal transduction pathways to regulate multiple cellular processes. In this study, using a germ cell culture system, we investigated (1) whether RA treatment activates any mitogen-activated protein kinase (MAPK) pathways in fetal germ cells at the time of sex differentiation, and (2) if this is the case, whether the corresponding RA-stimulated signaling pathway regulates Stra8 expression in fetal germ cells and their entry into meiosis. When XX germ cells at embryonic day (E) 12.5 were cultured with RA, the extracellular-signal-regulated kinase (ERK) 1/2 pathway was predominantly activated. MEK1/2 inhibitor (U0126) treatment suppressed the mRNA expressions of RA-induced Stra8 and meiotic marker genes (Rec8, Spo11, Dmc1, and Sycp3) in both XX and XY fetal germ cells. Furthermore, U0126 treatment dramatically reduced STRA8 protein levels and numbers of meiotic cells among cultured XX and XY fetal germ cells even in the presence of RA. Taken together, our results suggest the novel concept that the RA functions by stimulating the ERK1/2 pathway and that this activity is critical for Stra8 expression and meiotic progression in fetal germ cells.

Proliferative and Apoptotic Pathways in the Testis of Quail Coturnix coturnix during the Seasonal Reproductive Cycle

“…Similarly, a positive correlation between ERK1/2 activation and the increased number of cells positive for SYCP3 was observed in mouse testis in a previous study [45], which also demonstrated that Akt-1 inhibition abolished SYCP3 induction and the meiotic entry of postnatal mouse male germ cells [56]. Furthermore, inhibition of ERK1/2 was reported to suppress the genic expression of SYCP3 in cultured fetal germ cells [74]. Therefore, the findings of the present study are evidence for the local regulation of quail spermatogenesis via ERK/Akt-1 activation or inhibition during the reproductive cycle.…”

Ligand–Receptor Interactions Elucidate Sex-Specific Pathways in the Trajectory From Primordial Germ Cells to Gonia During Human Development

“…(Figures 4A,B and Supplementary Figure 2B), whereas punctate nuclear pERK (pMAPK1/2) was observed in somatic and germ cells of both sexes (Figures 4A,B; control in Supplementary Figure 3A), suggesting some degree of RTK activation in all cells (Figure 4C). The functional significance of the strong cytoplasmic accumulation of total ERK (MAPK1/2) in GONs remains to be further elucidated but could prepare GONs for meiotic entry (after RA signaling) (Kim et al, 2019). In agreement, leptotene/zygotene OGONs show some degree of nuclear ERK/pERK (Figure 4B).…”

“…ERK1 and ERK2 are required for oocyte maturation (Su et al, 2003;Fan et al, 2009). Moreover, it has been reported that treatment with RA activates ERK1/2 signaling in mouse OGONs (12 dpf) and that this is required to upregulate RA-induced Stra8, a key initiator of meiosis (Kim et al, 2019). The role of ERK activation in C. elegans germ cells has also been linked to meiotic progression, inducing phosphorylation of HTP1 (in human HORMAD1) and SYP-2 (in human SYCEs), which controls the assembly and maintenance of the synaptonemal complex (Nadarajan et al, 2016;Das et al, 2020).…”

PI3K/PTEN/AKT Signaling Pathways in Germ Cell Development and Their Involvement in Germ Cell Tumors and Ovarian Dysfunctions

“…Activated KIT also catalyzes direct phosphorylation of substrate proteins. Among the major signaling pathways ultimately activated by the KL/KIT including RAS-RAF-MEK-ERK, PLCγ, Src, and PI3K/AKT, these two latter are probably the most important to sustain PGC survival and take part in their active migration toward the gonadal anlages [ 22 , 23 , 24 ]. Interestingly, we found that the binding of 17-β-estradiol to its receptor ERα was also able to induce a rapid PI3K-dependent AKT phosphorylation in mouse PGCs [ 25 ].…”

“…In the same paper, a novel role for KL as the PGC chemoattractant and for PI3K/AKT and Src kinase, as players involved in the activation of the PGC migratory machinery, were demonstrated. In addition, evidence for two other possibly PI3K-dependent KL/KIT action on PGCs, adhesion to somatic cells [ 22 ], and survival, this latter, due to a reduction in the expression of the pro-apoptotic Bax gene, have been previously reported [ 23 , 24 ]. Gu’s group [ 15 ] found that the membrane-bound form of KL maintained a high local concentration for mouse PGC motility and defined their region of migration.…”