Low WIP1 Expression Accelerates Ovarian Aging by Promoting Follicular Atresia and Primordial Follicle Activation

Our previous study demonstrated that ovarian wild-type P53-induced phosphatase 1 (WIP1) expression decreased with age. We hypothesized that WIP1 activity was related to ovarian aging. The role of WIP1 in regulating ovarian aging and its mechanisms remain to be elucidated. Adult female mice with or without WIP1 inhibitor (GSK2830371) treatment were divided into three groups (Veh, GSK-7.5, GSK-15) to evaluate the effect of WIP1 on ovarian endocrine and reproductive function and the ovarian reserve. In vitro follicle culture and primary granulosa cell culture were applied to explore the mechanisms of WIP1 in regulating follicular development. This study revealed that WIP1 expression in atretic follicle granulosa cells is significantly lower than that in healthy follicles. Inhibiting WIP1 phosphatase activity in mice induced irregular estrous cycles, caused fertility declines, and decreased the ovarian reserve through triggering excessive follicular atresia and primordial follicle activation. Primordial follicle depletion was accelerated via PI3K-AKT-rpS6 signaling pathway activation. In vitro follicle culture experiments revealed that inhibiting WIP1 activity impaired follicular development and oocyte quality. In vitro granulosa cell experiments further indicated that downregulating WIP1 expression promoted granulosa cell death via WIP1-p53-BAX signaling pathway-mediated apoptosis. These findings suggest that appropriate WIP1 expression is essential for healthy follicular development, and decreased WIP1 expression accelerates ovarian aging by promoting follicular atresia and primordial follicle activation.

 

Comments:

It appears you're summarizing a scientific study on the role of wild-type P53-induced phosphatase 1 (WIP1) in ovarian aging and follicular development. Based on your summary, the study investigated the relationship between WIP1 activity and ovarian aging in mice. Here's a breakdown of the key findings and implications of the study:

### Key Findings:

1. **Decreased WIP1 Expression with Age:** The study confirmed that WIP1 expression decreases with age in the ovaries, indicating a potential link between WIP1 and ovarian aging.

2. **Role of WIP1 in Follicular Development:** Lower WIP1 expression was observed in atretic (dying) follicles compared to healthy ones, suggesting that appropriate WIP1 levels are crucial for healthy follicular development.

3. **Effect of WIP1 Inhibition in Mice:**
   - *Irregular Estrous Cycles:* Inhibiting WIP1 activity led to irregular estrous cycles in mice.
   - *Fertility Decline:* Mice with inhibited WIP1 activity showed a decline in fertility.
   - *Decreased Ovarian Reserve:* WIP1 inhibition caused a reduction in the ovarian reserve, likely due to excessive follicular atresia and premature activation of primordial follicles.

4. **Mechanisms of WIP1 in Ovarian Aging:**
   - *PI3K-AKT-rpS6 Signaling Pathway Activation:* WIP1 inhibition accelerated primordial follicle depletion through the activation of the PI3K-AKT-rpS6 signaling pathway.
   - *Impact on Follicular Development and Oocyte Quality:* In vitro experiments demonstrated that inhibiting WIP1 activity impaired follicular development and reduced oocyte quality.
   - *Granulosa Cell Death:* Downregulation of WIP1 expression promoted granulosa cell death through the WIP1-p53-BAX signaling pathway-mediated apoptosis.

### Implications and Conclusion:

- **WIP1 and Healthy Follicular Development:** The study highlights the importance of appropriate WIP1 expression for healthy follicular development in ovaries.

- **Accelerated Ovarian Aging:** Decreased WIP1 expression accelerates ovarian aging by promoting excessive follicular atresia and premature activation of primordial follicles, leading to a diminished ovarian reserve and reduced fertility.

- **Potential Therapeutic Target:** WIP1 could be a potential therapeutic target for interventions aiming to slow down ovarian aging and preserve fertility in females.

This research sheds light on the intricate mechanisms involved in ovarian aging and provides valuable insights into potential therapeutic approaches for age-related fertility decline.

Related Products

Cat.No.	Product Name	Information
S7573	GSK2830371	GSK2830371 is an orally active, allosteric Wip1 phosphatase inhibitor with IC50 of 6 nM.

Related Targets

phosphatase