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Published on: September 28, 2017
Loss-of-function mutations with circadian rhythm regulator Per1/Per2 lead to premature ovarian insufficiency†
Yating Zheng1, Chao Liu1, Yan Li1
1Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Abstract:
The mechanism underlying premature ovarian insufficiency remains incompletely understood. Here we report that mice with Per1m/m; Per2m/m double mutations display a decrease in female fertility starting approximately at 20 weeks old, with significantly less pups born from 32 weeks old onwards. Histological analysis revealed that a significant reduction of ovarian follicles was observed in the Per1/Per2 mutants compared with the littermate controls examined at 26 and 52 weeks old, while the difference was not statistically significant between the two groups at 3 and 8 weeks old. We further showed that vascular development including the ovarian follicle associated vascular growth appeared normal in the Per1/Per2 mutant mice, although clock genes were reported to regulate angiogenesis in zebrafish. The findings imply that loss-of-function mutations with Per1/Per2 result in a premature depletion of ovarian follicle reserve leading to the decline of reproductive capacity.
Insights
Loss-of-function mutations in Per1 and Per2 genes cause premature ovarian insufficiency in mice. This leads to reduced fertility and a depleted ovarian follicle reserve by middle age.
Area of Science:
- Reproductive biology
- Chronobiology
- Genetics
Background:
- Premature ovarian insufficiency (POI) affects female reproductive health, but its underlying mechanisms are not fully understood.
- Circadian clock genes, including Period 1 (Per1) and Period 2 (Per2), play crucial roles in various physiological processes.
Purpose of the Study:
- To investigate the role of Per1 and Per2 clock genes in female fertility and ovarian function.
- To determine if mutations in Per1 and Per2 lead to premature ovarian insufficiency.
Main Methods:
- Generation and analysis of double mutant mice lacking functional Per1 and Per2 genes (Per1m/m; Per2m/m).
- Assessment of female fertility by monitoring pup production over time.
- Histological examination of ovarian follicles at different ages (3, 8, 26, and 52 weeks).
- Evaluation of ovarian vascular development in mutant mice.
Main Results:
- Per1m/m; Per2m/m mutant mice exhibited decreased female fertility starting around 20 weeks of age.
- A significant reduction in ovarian follicles was observed in mutants at 26 and 52 weeks, but not at 3 or 8 weeks.
- Ovarian vascular development appeared normal in mutant mice, despite known roles of clock genes in angiogenesis.
Conclusions:
- Loss-of-function mutations in Per1 and Per2 contribute to premature ovarian insufficiency.
- These mutations lead to a premature depletion of the ovarian follicle reserve, ultimately reducing reproductive capacity.
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