CDC42 controls the activation of primordial follicles by regulating PI3K signaling in mouse oocytes

Abstract

BackgroundIn mammalian females, progressive activation of dormant primordial follicles in adulthood is crucial for the maintenance of the reproductive lifespan. Misregulated activation of primordial follicles leads to various ovarian diseases, such as premature ovarian insufficiency (POI). Although recent studies have revealed that several functional genes and pathways, such as phosphoinositide 3-kinase (PI3K) signaling, play roles in controlling the activation of primordial follicles, our understanding of the molecular networks regulating the activation progress is still incomplete.ResultsHere, we identify a new role for cell division cycle 42 (CDC42) in regulating the activation of primordial follicles in mice. Our results show that CDC42 expression increases in oocytes during the activation of primordial follicles in the ovary. Disruption of CDC42 activity with specific inhibitors or knockdown of Cdc42 expression significantly suppresses primordial follicle activation in cultured mouse ovaries. Conversely, the follicle activation ratio is remarkably increased by overexpression of CDC42 in ovaries. We further demonstrate that CDC42 governs the process of primordial follicle activation by binding to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (p110β) and regulating the expression levels of PTEN in oocytes. Finally, we extend our study to potential clinical applications and show that a short-term in vitro treatment with CDC42 activators could significantly increase the activation rates of primordial follicles in both neonatal and adult mouse ovaries.ConclusionOur results reveal that CDC42 controls the activation of primordial follicles in the mammalian ovary and that increasing the activity of CDC42 with specific activators might improve the efficiency of in vitro activation approaches, opening avenues for infertility treatments.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0541-4) contains supplementary material, which is available to authorized users.

Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

“…Studies have shown that when FOXO3 is in the nucleus of the oocyte, it will maintain the follicles in a quiescent state. However, when FOXO3 is phosphorylated, it translocates out of the nucleus to promote follicle activation [ 28 ]. To confirm this, we performed IHC staining of FOXO3 ( Figure 5 A).…”

“…Combined with the GO analysis of DEGs ( Figure 1 D), these results further confirm with single-cell data that the PTEN-AKT-FOXO3a signaling pathway is the key pathway for follicular activation. Next, we predicted the upstream factors that might be associated with follicle activation ( Table S3 ) and selected chemical drugs with the highest z-scores and verified their effects in the ovarian in vitro culture system, which is commonly used to study primordial follicle activation [ 21 , 28 , 38 ]. Among these drugs, curcumin was found to have a protective effect on the ovarian reserve.…”

KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells

“…But pcDNA3.1-KISS1 significantly decreased the mRNA levels of FOXO3, TSC2, and BAD (Figure 2C), which are the important downstream genes of the PI3K signaling pathway. Previous studies recommend that PIK3CG exhibits significant DNA copy number gains in ovarian cancer, compared to normal ovary in humans [42], PIK3C1 promotes the activation of primordial follicles [43], and moreover, in PDK1 depletion in oocytes depletes the majority of primordial follicles around the onset of sexual maturity and causes premature ovarian failure in mice [44]. In addition, FOXO3 depletion in GCs disrupts the normal ovarian follicular growth in mice [45], and a lower FOXO3 mRNA expression in GCs may lead to infertility in women [46].…”

The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles

“…The viral supernatants were collected via ultracentrifugation. As previously reported [ 61 , 62 ], we used a glass needle to inject the lentiviral vectors into the cortex of the neonatal ovaries at 1 dpp, selecting at least three parts. For each ovary, at least 0.3 μL of the lentiviral suspension (1×10 8 IU/mL) was injected.…”