Role Of Circadian Gene In Female Fertility And Vascular Growth

The circadian rhythms of mammalians consists of the master circadian oscillator which locates in suprachiasmatic nuclei(SCN) of the brain and peripheral circadian oscillators. The molecular basis of these circadian oscillations is a feedback loop composed of positive and negative regulating factors including Clock, Bmal1 and Per, Cry respectively. The circadian clock plays important roles in regulating various biological processes, including fertility. The characteristics of the ovarian cycle include the follicular development, ovulation, corpus luteum formation and degeneration. The process of ovarian cycles is accompanied by the active vascular growth and regression. In this study, we employed genetically modified mouse models including Per1, Per2 single and double knockout and also Bmal1 null mice to investigate their functions in the female reproduction and vascular growth. The major findings include: 1) Deletion of Per1/2 led to a significant decrease of litter size, especially for mice older than 6 month. 2) Histological analysis of ovaries by H&E staining revealed that Per1/2 double knockout mice had similar number of primordial, primary, secondary or antral ovarian follicles at the stage of 2-month old in comparison with those of control littermates. However, there was a significant decrease in the number of ovarian follicles at stages of 6 month-old and 12 month-old between the two groups. The follicular depletion of Per1/2 null mice was faster than that of control mice as aging. But we did not observe any significant difference in the estradiol level at different ages of Per1/2 knockout and control mice. We also performed the gene expression profiling in ovaries from Per1/2 knockout and control mice and the detailed analysis is still ongoing. 3) Although previous studies showed that Per2 and Bmal1 played important roles in the regulation of VEGF-dependent angiogenesis in zebrafish, we did not observe any obvious difference in both blood and lymphatic vascular growth in ovary, uterus and other organs of mice deficient of Per1, Per2, Per1/2 or Bmal1 compared with the control mice.In summary, deletion of Per1/2 may cause the premature aging of ovary, which may account for the reduced female fertility. The detailed mechanism remains further investigation.