Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation

Many integral membrane proteins might act as indispensable coordinators in specific functional microdomains to maintain the normal operation of known receptors, such as Notch. Gm364 is a multi-pass transmembrane protein that has been screened as a potential female fertility factor. However, there have been no reports to date about its function in female fertility. Here, we found that global knockout of Gm364 decreased the numbers of primordial follicles and growing follicles, impaired oocyte quality as indicated by increased ROS and gamma-H2AX, decreased mitochondrial membrane potential, decreased oocyte maturation, and increased aneuploidy. Mechanistically, Gm364 directly binds and anchors MIB2, a ubiquitin ligase, on the membrane. Subsequently, membrane MIB2 ubiquitinates and activates DLL3. Next, the activated DLL3 binds and activates Notch2, which is subsequently cleaved within the cytoplasm to produce NICD2, the intracellular active domain of Notch2. Finally, NICD2 can directly activate AKT within the cytoplasm to regulate oocyte meiosis and quality.

Automated summary

This study reveals the critical role of Gm364 in female fertility, where its knockout results in decreased follicle numbers, impaired oocyte quality, reduced oocyte maturation, and increased aneuploidy. Mechanistically, Gm364 interacts with MIB2 to activate the Notch2-AKT signaling pathway, influencing oocyte meiosis and quality.