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Granulosa cell mevalonate pathway abnormalities contribute to oocyte meiotic defects and aneuploidy.

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Author information

Affiliations

  • 1. Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
      Authors
    • Liu C 1
    • Yan G 1
    • Wang S 1
    • Li S 1
    • Tang X 1
    • Li Y 1
    • Cai C 1
    • Liu W 1
    • Fang J 1
    • Zhang Y 1
    • Zhou J 1
    • Zhen X 1
    • Hu Y 1
    • Sun H 1
    • Ding L 1
    (15 authors)
  • 2. Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
      Authors
    • Zuo W 2
    • Bian Q 2
    (2 authors)
  • 3. State Key Laboratory of Stem Cell and Reproductive Biology, Chinese Academy of Sciences, Beijing, China.
      Authors
    • Sun S 3
    • Wang Z 3
    (2 authors)
  • 4. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School, Nanjing University, Nanjing, China.
      Authors
    • Wang H 4
    • Feng T 4
    • Li C 4
    (3 authors)

ORCIDs linked to this article

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Nature Aging, 15 May 2023, 3(6):670-687
https://doi.org/10.1038/s43587-023-00419-9 PMID: 37188792 

Abstract 

With aging, abnormalities during oocyte meiosis become more prevalent. However, the mechanisms of aging-related oocyte aneuploidy are not fully understood. Here we performed Hi-C and SMART-seq of oocytes from young and old mice and reveal decreases in chromosome condensation and disrupted meiosis-associated gene expression in metaphase I oocytes from aged mice. Further transcriptomic analysis showed that meiotic maturation in young oocytes was correlated with robust increases in mevalonate (MVA) pathway gene expression in oocyte-surrounding granulosa cells (GCs), which was largely downregulated in aged GCs. Inhibition of MVA metabolism in GCs by statins resulted in marked meiotic defects and aneuploidy in young cumulus-oocyte complexes. Correspondingly, supplementation with the MVA isoprenoid geranylgeraniol ameliorated oocyte meiotic defects and aneuploidy in aged mice. Mechanically, we showed that geranylgeraniol activated LHR/EGF signaling in aged GCs and enhanced the meiosis-associated gene expression in oocytes. Collectively, we demonstrate that the MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes, and age-associated MVA pathway abnormalities contribute to oocyte meiotic defects and aneuploidy.

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Read article at publisher's site: https://doi.org/10.1038/s43587-023-00419-9

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National Natural Science Foundation of China (National Science Foundation of China) (4)