Cyclin-dependent kinase 6 (CDK6) as a potent regulator of the ovarian primordial-to-primary follicle transition

by Selleckchem | Dec 11 2023

Introduction: Ovarian follicle development requires tight coordination between several factors to initiate folliculogenesis to generate a mature and fertile egg. Studies have shown that cell cycle factors might contribute to follicle development, hover specific knowledge on individual CDKs and follicle activation has not been investigated. Among cell cycle regulators, CDK6 is a key player through binding to cyclin D resulting DNA synthesis and genome duplication. Interestingly, the CDK6 gene is differentially expressed in oocytes and granulosa cells from human primordial and primary follicles, which suggest a potential role of CDK6 in the primordial-to-primary transition. In this study, we investigated the potential regulatory role of CDK6 in progression of primordial to primary follicle transition using BSJ-03-123 (BSJ), a CDK6-specific degrader.

Methods: In mouse ovarian in vitro culture, BSJ reduced the activation of primordial follicles, and reduced follicle development. As a next step, we examined the egg maturation read-out and found that BSJ-treated follicles matured to competent MII eggs with resumption of first meiosis, comparable with the control group.

Results: Noteworthy, it appears that inhibition of CDK6 did increase number of apotoptic cells, articular in the granulosa cells, but had no impact on ROS level of cultured ovaries compared to control group, indicating that the cells were not stressed. Oocyte quality thus appeared safe.

Discussion: The results of this study indicate that CDK6 plays a role in the primordial-to-primary transition, suggesting that cell cycle regulation is an essential part of ovarian follicle development.

Comments:

**Introduction:**

Ovarian follicle development is a complex process requiring precise coordination of various factors to initiate and progress through folliculogenesis, ultimately leading to the production of mature and fertile eggs. While studies have hinted at the involvement of cell cycle factors in this intricate process, specific research on individual cyclin-dependent kinases (CDKs) and their contribution to follicle activation has been lacking. Among these cell cycle regulators, CDK6 stands out as a crucial player, forming complexes with cyclin D and facilitating DNA synthesis and genome duplication. Interestingly, the CDK6 gene exhibits differential expression in oocytes and granulosa cells derived from human primordial and primary follicles, suggesting a potential role for CDK6 in the transition from primordial to primary follicles. This study delves into exploring the regulatory role of CDK6 in this pivotal stage of follicular development, employing BSJ-03-123 (BSJ), a CDK6-specific degrader.

**Methods:**

In this investigation, mouse ovarian tissues were subjected to in vitro culture with the application of BSJ. The effects of BSJ on the activation of primordial follicles and subsequent follicle development were meticulously studied. Subsequently, the study assessed the maturation status of eggs derived from BSJ-treated follicles, focusing on the resumption of the first meiotic division, a crucial indicator of egg competency.

**Results:**

The results of the study demonstrated that BSJ treatment significantly reduced the activation of primordial follicles and impeded their development. However, intriguingly, the eggs derived from these treated follicles exhibited competent maturation to the metaphase II (MII) stage, indicating the resumption of the first meiotic division comparable to the control group. Notably, while inhibition of CDK6 led to an increase in apoptotic cells, particularly within the granulosa cell population, it had no significant impact on the levels of reactive oxygen species (ROS) in the cultured ovaries. This suggests that despite the increase in apoptotic cells, the cells were not under significant stress, preserving the quality of the oocytes.

**Discussion:**

These findings shed light on the pivotal role of CDK6 in the transition from primordial to primary follicles, underscoring the importance of precise cell cycle regulation in ovarian follicle development. The study suggests that disrupting the activity of CDK6 using BSJ hampers the activation and progression of primordial follicles, highlighting the intricate nature of folliculogenesis and the delicate balance required for successful egg maturation. This research not only advances our understanding of the molecular mechanisms governing ovarian follicle development but also paves the way for potential therapeutic interventions targeting CDK6 to address fertility-related issues and reproductive disorders.