In a manuscript published in PNAS, Meinsohn et al. show that AMH/MIS inhibits granulosa cells, ovarian surface epithelial cells, and ovarian stromal cells in neonatal mouse and rat ovaries. The transcriptional programs regulated in these cell types were identified by scRNAseq, and validated by qPCR and RNAish. In addition to inhibiting proliferation, genes associated with stemness (Lgr5, Aldh1a1) were repressed in the surface epithelium, which also shared perturbation of similar gene networks observed in the granulosa cells (Id2, Id3, Smad6, etc.). In contrast, stromal cell types, which express little to no MISR2 receptor had a unique response to treatment, which may be related to disruption of cell-cell communication with their granulosa and epithelial neighbours, including IGF and BMP/TGFb signalling. Surprisingly we identified few perturbation in germ cells, suggesting the follicle quiescence is mainly driven by regulatory programs in the granulosa cells. Futhermore, we characterized a new follicular phenotype in response to MIS treatment in which oocytes excaped repression and grew, but granulosa cells failed to mature in tandem, giving rise to mismatched oocyte-follicle development. This repressive effect of MIS on preantral granulosa cell maturation may complement the inhibition of primordial follicle activation to maintain ovarian quiescence. Furthermore we identified regulatory networks, such as immediate-early genes which were associated with granulosa cell quiescence in control females, and further activated when treated with MIS.

Press releases describing the potential clinical applications can be found here:

MIS hormone shown to suppress ovarian follicle development

New understanding of ovarian follicle development may lead to novel reproductive therapies