Oocyte aging
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In humans, all oocytes begin their development in-utero but arrest for decades in the middle of this process, leading to a rapid age-related increase in meiotic division failure. This failure is the leading cause for naturally occurring miscarriages and birth defects (e.g. Down syndrome). In most women most of the oocyte cannot lead to the birth of healthy baby after the age of 35. Currently there is no way to improve the quality of aging oocytes. We asked what are the changes that occur in germline of aging worms? We monitored young (1 day adult), mature (4 days adult), old (8 days adult), and menopaused (10 days adult) worms, and found several processes that change during aging. The common thing to all?
They were all previously reported to change in worms with aberrant with MAP Kinase signaling. In line with this, activation of this pathway changes during aging, and it is activated in may stages and not just late pachytene and mature oocytes as it does in young adults:
IF images of gonads at indicated ages stained with DAPI (blue) and activated MPK-1/Erk (red). Quantification of fluorescence intensity averages at different meiotic stages are shown below each image.
This has led us to hypothesize that germline aging can be controlled by attenuating MAPK signaling. Embryo viability, which is an established marker for oocyte quality, is lower in mutants with higher MAPK activation:
A: Illustration of experimental design. B: Embryonic viability of WT and mutants with higher MAPK signaling following 24 hours of oocyte arrest.
Similarly, reducing MAPK signaling by RNAi depletion or specific inhibitors significantly improved oocytes’ viability and increased their size:
A: Illustration of experimental design. B-D: Embryonic viability of WT and mpk-1 ts strain (B) mpk-1 RNAi (C) and in the presence of MAPK inhibitor (D), following 24 hours of oocyte arrest.
Thus, we suggest that MAPK stands at the base of the gonadal control of oocyte aging. Read more.
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Open questions and current work:
1. Is MAPK activated and repressed by external cues?
2. What are the downstream targets of MAPK?
3. Can we improve human oocyte quality by controlling cellular signals?
