P4 down-regulates Jagged2 and Notch1 expression during primordial folliculogenesis

Abstract

Nest breakdown and primordial folliculogenesis of the mouse ovary can be inhibited by progesterone (P4) and Notch signaling inhibitors. However, the relationship between these two signals during this process remains unknown. In the present study, transcript levels of Jagged2, Notch1, and their target, Hey2, increased markedly in ovaries during the beginning stage of folliculogenesis (17.5 days post coitus (dpc) to birth). Maternal P4 levels decreased simultaneously. We found that maternal midpregnancy P4 levels significantly inhibited Jagged2, Notch1, and Hey2 expression, and follicle formation in vitro. Maintaining high maternal P4 levels by daily injection also significantly suppressed the expression of Jagged2, Notch1, and Hey2, and follicle formation during late pregnancy. Based on immunohistochemistry, Jagged2 was localized in oocytes and Notch1 was strongly stained in pre-granulosa cells in 19.5 dpc ovaries. Suppression of their function by antibody addition and RNAi markedly inhibited nest breakdown and follicle formation. Taken together, these results demonstrate that maternal P4 levels during midpregnancy can inhibit the expression of Jagged2 and Notch1, which are involved in primordial folliculogenesis, in the mouse fetal ovary.

Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis

“…However, disorganization of primordial follicle pool does not occur in nPRs-null mice27. Moreover, nPRs antagonist mifepristone (RU486) cannot abolish P4-induced inhibition of primordial follicle formation911. In the current study, qRT-PCR showed that mRNA levels of nPRs were the lowest (less than one-hundred of the mRNA levels of Pgrmc1 ) among all P4 receptors in 17.5 dpc ovaries.…”

“…In murine perinatal ovaries, precipitous decline of high P4 levels and assembly of abundant primordial follicles occur simultaneously after labor8910. P4 attenuates cyst breakdown and primordial follicle formation both in vivo and in vitro 1112.…”

“…The decrease in P4 levels after birth abolishes this suppressive effect, resulting in extensive follicle formation. Although Notch signaling pathway and tumor necrosis factor α are suggested to mediate the effect of P4 on follicle formation915, the exact mechanisms underlying this effect remain unclear.…”

Follistatin288 Regulates Germ Cell Cyst Breakdown and Primordial Follicle Assembly in the Mouse Ovary

“…Female mice with conditional deletion of the Notch2 gene in somatic granulosa cells of the ovary exhibited multi-oocyte follicles which were resulted from defects in breakdown of the primordial germ-cell nests [36]. Previous results in our lab also showed that down-regulation of Jagged2 and Notch1 by RNAi (RNA interference) inhibited germ cell nest breakdown and primordial follicle formation in vitro [8]. Besides, interactions between Notch and the ACT signaling pathway have also been described [37–40].…”

“…For instance, in the neonatal mouse ovary, both estradiol and progesterone are critical for inhibiting nest breakdown and primordial follicle formation [6–7]. In addition, progesterone has been shown to prevent nest breakdown through down-regulation of Notch signaling [8]. Finally, transforming growth factor-β (TGF-β) family members, such as TGF-β, activin (ACT) and inhibin (INH) have multiple functions in vivo during early folliculogenesis [5, 9–12].…”