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  • Title: Involvement of SIRT3-GSK3β deacetylation pathway in the effects of maternal diabetes on oocyte meiosis.
    Author: Xin Y, Jin Y, Ge J, Huang Z, Han L, Li C, Wang D, Zhu S, Wang Q.
    Journal: Cell Prolif; 2021 Jan; 54(1):e12940. PubMed ID: 33107080.
    Abstract:
    OBJECTIVES: It has been widely reported that maternal diabetes impairs oocyte quality. However, the responsible mechanisms remain to be explored. In the present study, we focused on whether SIRT3-GSK3β pathway mediates the meiotic defects in oocytes from diabetic mice. MATERIALS AND METHODS: GSK3β functions in mouse oocyte meiosis were first detected by targeted siRNA knockdown. Spindle assembly and chromosome alignment were visualized by immunostaining and analysed under the confocal microscope. PCR-based site mutation of specific GSK3β lysine residues was used to confirm which lysine residues function in oocyte meiosis. siRNA knockdown coupled with cRNA overexpression was performed to detect SIRT3-GSK3β pathway functions in oocyte meiosis. Immunofluorescence was performed to detect ROS levels. T1DM mouse models were induced by a single intraperitoneal injection of streptozotocin. RESULTS: In the present study, we found that specific depletion of GSK3β disrupts maturational progression and meiotic apparatus in mouse oocytes. By constructing site-specific mutants, we further revealed that acetylation state of lysine (K) 15 on GSK3β is essential for spindle assembly and chromosome alignment during oocyte meiosis. Moreover, non-acetylation-mimetic mutant GSK3β-K15R is capable of partly preventing the spindle/chromosome anomalies in oocytes with SIRT3 knockdown. A significant reduction in SIRT3 protein was detected in oocytes from diabetic mice. Of note, forced expression of GSK3β-K15R ameliorates maternal diabetes-associated meiotic defects in mouse oocytes, with no evident effects on oxidative stress. CONCLUSION: Our data identify GSK3β as a cytoskeletal regulator that is required for the assembly of meiotic apparatus, and discover a beneficial effect of SIRT3-dependent GSK3β deacetylation on oocyte quality from diabetic mice.
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