Fig 7. RA noncanonically activates the ERK1/2 pathway to regulate Stra8 expression and meiotic initiation in fetal germ cells.

In general, RA canonically binds to nuclear RARs to control the transcriptional expression of RA target genes. Based on our results, we propose a novel concept that RA signaling also functions via an alternate signal transduction cascade in the cytoplasm, independent of the canonical pathway mediated by nuclear RARs, to control meiosis. In isolated XX and XY germ cells, external RA noncanonically stimulates the ERK1/2 signal transduction pathway in the cytoplasm. The phosphorylated ERK1/2 moves to the nucleus and contributes to Stra8 expression to stimulate meiotic initiation. Although the details of the molecular features of this proposed alternate RA-stimulated ERK1/2 pathway remain unclear, it is possible that crosstalk between the canonical and noncanonical activities of RA impact the transcriptional regulation of Stra8 to induce entry into meiosis.