GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice

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Abstract
Female mammals have a limited reproductive lifespan determined by the size of the primordial follicle pool established perinatally. Over two thirds of fetal oocytes are abolished via programmed cell death during early folliculogenesis. However, the underlying mechanisms governing fetal oocyte attrition remain largely elusive. Here, we demonstrate that glycogen synthase kinase-3 beta (GSK-3β) is indispensable for fetal oocyte maintenance during meiotic prophase I in mice. In vitro inhibition of GSK-3β activity or in vivo conditional deletion of Gsk-3β in the germline led to a dramatic loss of fetal oocytes via apoptosis, which subsequently resulted in a reduced capacity of the primordial follicle pool. Inhibition of GSK-3β also impeded meiotic progression in fetal oocytes and led to a deficiency in DNA double-strand break (DSB) repair associated with premature upregulation of Tap63, the major genome guardian of the female germline, following GSK-3β inhibition in fetal ovaries. Mechanistically, we demonstrated that aberrant nuclear translocation of β-catenin was responsible for the abnormal expression of TAp63 and global fetal oocyte attrition following GSK-3β inhibition. In summary, GSK-3β was essential for sustaining fetal oocyte survival and folliculogenesis via fine-tuning the cytoplasmic-nuclear translocation of β-catenin, which in turn modulates timely TAp63 expression during meiotic prophase I in mice. Our study provides a perspective on the physiological regulatory role of DNA damage checkpoint signaling in fetal oocyte guardianship and female fertility.
Funding Information
  • National Key Research & Developmental Program of China (2018YFC1003700, 2018YFC1003700, 2017YFC1001100, 2018YFC1003801)
  • National Basic Research Program of China (2014CB943202, 2013CB945501, 2013CB945501)
  • National Natural Science Foundation of China (31872792, 31371448, 31571540)
  • Beijing Natural Science Foundation (5182015, 7182090)
  • Project of State Key Laboratory of Agrobiotechnology (2015SKLAB4-1, 2016SKLAB-1)
  • Institution of Higher Education Projects of Building First-class Discipline Construction in Ningxia Region (Biology (NXYLXK2017B05)

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