Risal Sanjiv, Zhang Jingjing, Adhikari Deepak, Liu Xiaoman, Shao Jingchen, Hu Mengwen, Busayavalasa Kiran, Tu Zhaowei, Chen Zijiang, Kaldis Philipp, Liu Kui
Department of Chemistry and Molecular Biology, University of Gothenburg , Gothenburg, Sweden.
Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University , Melbourne, Victoria, Australia.
Cell Discov. 2017 Feb 7;3:16052. doi: 10.1038/celldisc.2016.52. eCollection 2017.
In mammals, primordial germ cells (PGCs) are the embryonic cell population that serve as germ cell precursors in both females and males. During mouse embryonic development, the majority of PGCs are arrested at the G2 phase when they migrate into the hindgut at 7.75-8.75 dpc (days post coitum). It is after 9.5 dpc that the PGCs undergo proliferation with a doubling time of 12.6 h. The molecular mechanisms underlying PGC proliferation are however not well studied. In this work. Here we studied how MASTL (microtubule-associated serine/threonine kinase-like)/Greatwall kinase regulates the rapid proliferation of PGCs. We generated a mouse model where we specifically deleted in PGCs and found a significant loss of PGCs before the onset of meiosis in female PGCs. We further revealed that the deletion of in PGCs did not prevent mitotic entry, but led to a failure of the cells to proceed beyond metaphase-like stage, indicating that MASTL-mediated molecular events are indispensable for anaphase entry in PGCs. These mitotic defects further led to the death of -null PGCs by 12.5 dpc. Moreover, the defect in mitotic progression observed in the -null PGCs was rescued by simultaneous deletion of (α subunit of PP2A). Thus, our results demonstrate that MASTL, PP2A, and therefore regulated phosphatase activity have a fundamental role in establishing female germ cell population in gonads by controlling PGC proliferation during embryogenesis.
在哺乳动物中，原始生殖细胞（PGCs）是胚胎细胞群体，在雌性和雄性中均作为生殖细胞前体。在小鼠胚胎发育过程中，大多数PGCs在7.75 - 8.75天胚龄（受孕后天数）迁移到后肠时停滞在G2期。在9.5天胚龄之后，PGCs开始增殖，倍增时间为12.6小时。然而，PGCs增殖的分子机制尚未得到充分研究。在这项工作中。在这里，我们研究了MASTL（微管相关丝氨酸/苏氨酸激酶样）/Greatwall激酶如何调节PGCs的快速增殖。我们构建了一个在PGCs中特异性缺失的小鼠模型，发现雌性PGCs在减数分裂开始前PGCs显著减少。我们进一步发现，在PGCs中缺失并不会阻止有丝分裂的进入，但会导致细胞无法进入类似中期之后的阶段，这表明MASTL介导的分子事件对于PGCs进入后期是不可或缺的。这些有丝分裂缺陷进一步导致缺失的PGCs在12.5天胚龄时死亡。此外，通过同时缺失（PP2A的α亚基）可挽救在缺失的PGCs中观察到的有丝分裂进程缺陷。因此，我们的结果表明，MASTL、PP2A以及由此调节的磷酸酶活性在胚胎发育过程中通过控制PGCs增殖在性腺中建立雌性生殖细胞群体方面具有重要作用。
