GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice
Abstract Background 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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-03-01
|
| Series: | BMC Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12915-019-0641-9 |
| _version_ | 1811330648318672896 |
|---|---|
| author | Jia Wen Hao Yan Meina He Tuo Zhang Xinyi Mu Haibin Wang Hua Zhang Guoliang Xia Chao Wang |
| author_facet | Jia Wen Hao Yan Meina He Tuo Zhang Xinyi Mu Haibin Wang Hua Zhang Guoliang Xia Chao Wang |
| author_sort | Jia Wen |
| collection | DOAJ |
| description | Abstract Background 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. Results 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. Conclusions 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. |
| first_indexed | 2024-04-13T16:06:50Z |
| format | Article |
| id | doaj.art-65e35efd62a94cf4827da10113f5188b |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-04-13T16:06:50Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-65e35efd62a94cf4827da10113f5188b2022-12-22T02:40:23ZengBMCBMC Biology1741-70072019-03-0117111910.1186/s12915-019-0641-9GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in miceJia Wen0Hao Yan1Meina He2Tuo Zhang3Xinyi Mu4Haibin Wang5Hua Zhang6Guoliang Xia7Chao Wang8State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityFujian Provincial Key Laboratory of Reproductive Health Research, Medical College of Xiamen UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityState Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural UniversityAbstract Background 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s12915-019-0641-9DNA damage checkpointGSK-3βMeiotic prophase IOocytesPrimordial follicle |
| spellingShingle | Jia Wen Hao Yan Meina He Tuo Zhang Xinyi Mu Haibin Wang Hua Zhang Guoliang Xia Chao Wang GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice BMC Biology DNA damage checkpoint GSK-3β Meiotic prophase I Oocytes Primordial follicle |
| title | GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice |
| title_full | GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice |
| title_fullStr | GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice |
| title_full_unstemmed | GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice |
| title_short | GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice |
| title_sort | gsk 3β protects fetal oocytes from premature death via modulating tap63 expression in mice |
| topic | DNA damage checkpoint GSK-3β Meiotic prophase I Oocytes Primordial follicle |
| url | http://link.springer.com/article/10.1186/s12915-019-0641-9 |
| work_keys_str_mv | AT jiawen gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT haoyan gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT meinahe gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT tuozhang gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT xinyimu gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT haibinwang gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT huazhang gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT guoliangxia gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice AT chaowang gsk3bprotectsfetaloocytesfromprematuredeathviamodulatingtap63expressioninmice |