State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, Center of Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, 215002, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2308823. doi: 10.1002/advs.202308823. Epub 2024 Sep 17.
Asynchronous nuclear and cytoplasmic maturation in human oocytes is believed to cause morphological anomalies after controlled ovarian hyperstimulation. Vacuolar protein sorting 34 (VPS34) is renowned for its pivotal role in regulating autophagy and endocytic trafficking. To investigate its impact on oocyte development, oocyte-specific knockout mice (ZcKO) are generated, and these mice are completely found infertile, with embryonic development halted at 2- to 4-cell stage. This infertility is related with a disruption on autophagic/mitophagic flux in ZcKO oocytes, leading to subsequent failure of zygotic genome activation (ZGA) in derived 2-cell embryos. The findings further elucidated the regulation of VPS34 on the activity and subcellular translocation of RAS-related GTP-binding protein 7 (RAB7), which is critical not only for the maturation of late endosomes and lysosomes, but also for initiating mitophagy via retrograde trafficking. VPS34 binds directly with RAB7 and facilitates its activity conversion through TBC1 domain family member 5 (TBC1D5). Consistent with the cytoplasmic vacuolation observed in ZcKO oocytes, defects in multiple vesicle trafficking systems are also identified in vacuolated human oocytes. Furthermore, activating VPS34 with corynoxin B (CB) treatment improved oocyte quality in aged mice. Hence, VPS34 activation may represent a novel approach to enhance oocyte quality in human artificial reproduction.
人们认为，人类卵母细胞的核质成熟不同步会导致控制性卵巢过度刺激后的形态异常。液泡分选蛋白 34（VPS34）在调节自噬和内吞运输方面起着关键作用。为了研究其对卵母细胞发育的影响，生成了卵母细胞特异性敲除小鼠（ZcKO），这些小鼠完全不育，胚胎发育在 2-4 细胞阶段停滞。这种不育与 ZcKO 卵母细胞中自噬/线粒体自噬通量的破坏有关，导致随后衍生的 2 细胞胚胎合子基因组激活（ZGA）失败。研究结果进一步阐明了 VPS34 对 RAS 相关 GTP 结合蛋白 7（RAB7）活性和亚细胞易位的调节作用，这不仅对晚期内体和溶酶体的成熟至关重要，而且对通过逆行运输引发线粒体自噬也至关重要。VPS34 与 RAB7 直接结合，并通过 TBC1 结构域家族成员 5（TBC1D5）促进其活性转换。与 ZcKO 卵母细胞中观察到的细胞质空泡化一致，在空泡化的人类卵母细胞中也发现了多个囊泡运输系统的缺陷。此外，用 corynoxin B（CB）处理激活 VPS34 可改善老年小鼠的卵母细胞质量。因此，激活 VPS34 可能代表一种提高人类人工生殖中卵母细胞质量的新方法。
