GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice
GSK-3β protects fetal oocytes from premature death via modulating TAp63 expression in mice
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GSK-3β 通过调节小鼠中 TAp63 的表达来保护胎儿卵母细胞免于过早死亡
DOI：
10.1186/s12915-019-0641-9
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发表时间：
2019-03
期刊：
影响因子：
5.4
通讯作者：
Chao Wang
中科院分区：
文献类型：
--
作者：
Jia Wen;Hao Yan;Meina He;Tuo Zhang;Xinyi Mu;Haibin Wang;Hua Zhang;Guoliang Xia;Chao Wang
背景雌性哺乳动物的生殖寿命有限，这是由围生期建立的原始卵泡池的大小决定的。超过三分之二的胎儿卵母细胞在早期卵泡发生过程中通过程序性细胞死亡而死亡。结果在小鼠减数分裂前期，糖原合成酶-3β(GSK-3β)对胚胎卵母细胞的维持起着不可或缺的作用。在体外抑制GSK-3β活性或体内有条件地删除生殖系中的GSK-3β会导致胚胎卵母细胞通过细胞凋亡而急剧丧失，从而导致原始卵泡池容量的降低。抑制GSK-3β也阻碍了胚胎卵母细胞的减数分裂进程，并导致胚胎卵巢中GSK-3β抑制后，与Tap63(雌性生殖系的主要基因组守护者)过早上调相关的DNA双链断裂修复不足。结论在小鼠减数分裂前期，β-3β通过微调β胞质-核转位，调节β-Catenin的胞质-核转位，从而适时调控TAp63的表达，从而维持胚胎卵母细胞的存活和卵泡的发生。我们的研究为DNA损伤检查点信号在胎儿卵母细胞监护和女性生育中的生理调节作用提供了一个前景。
BackgroundFemale 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.ResultsHere, 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 ofGsk-3βin 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.ConclusionsIn 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.
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影响因子：
64.5
作者：
Tang WW;Dietmann S;Irie N;Leitch HG;Floros VI;Bradshaw CR;Hackett JA;Chinnery PF;Surani MA
通讯作者：
Surani MA
在发育中的小鼠卵母细胞中，通过对TAp63α磷酸化的时序调控，在减数分裂前期I阶段抵御DNA双链断裂诱导的死亡
影响因子：
5.3
作者：
Kim, Dal-Ah;Suh, Eun-Kyung
通讯作者：
Suh, Eun-Kyung
影响因子：
3.5
作者：
Chassot, Anne-Amandine;Ranc, Fariba;Chaboissier, Marie-Christine
通讯作者：
Chaboissier, Marie-Christine
影响因子：
2.7
作者：
Tohru Kimura;Toshinobu Nakamura;Kazushige Murayama;H. Umehara;Noriko Yamano;Shoko Watanabe;M. Taketo;T. Nakano
通讯作者：
Tohru Kimura;Toshinobu Nakamura;Kazushige Murayama;H. Umehara;Noriko Yamano;Shoko Watanabe;M. Taketo;T. Nakano
影响因子：
16
作者：
Kerr, Jeffrey B.;Hutt, Karla J.;Michalak, Ewa M.;Cook, Michele;Vandenberg, Cassandra J.;Liew, Seng H.;Bouillet, Philippe;Mills, Alea;Scott, Clare L.;Findlay, Jock K.;Strasser, Andreas
通讯作者：
Strasser, Andreas