Institute of Women, Children and Reproductive Health, Shandong University, 250012, Jinan, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, 250012, Jinan, Shandong, China.
EMBO Rep. 2024 Nov;25(11):4876-4897. doi: 10.1038/s44319-024-00267-7. Epub 2024 Oct 2.
CHK1 mutations could cause human zygote arrest at the pronuclei stage, a phenomenon that is not well understood at the molecular level. In this study, we conducted experiments where pre-pronuclei from zygotes with CHK1 mutation were transferred into the cytoplasm of normal enucleated fertilized eggs. This approach rescued the zygote arrest caused by the mutation, resulting in the production of a high-quality blastocyst. This suggests that CHK1 dysfunction primarily disrupts crucial biological processes occurring in the cytoplasm. Further investigation reveals that CHK1 mutants have an impact on the F-actin meshwork, leading to disturbances in pronuclear envelope breakdown. Through co-immunoprecipitation and mass spectrometry analysis of around 6000 mouse zygotes, we identified an interaction between CHK1 and MICAL3, a key regulator of F-actin disassembly. The gain-of-function mutants of CHK1 enhance their interaction with MICAL3 and increase MICAL3 enzymatic activity, resulting in excessive depolymerization of F-actin. These findings shed light on the regulatory mechanism behind pronuclear envelope breakdown during the transition from meiosis to the first mitosis in mammals.
CHK1 突变可能导致人类受精卵在原核阶段停滞，这种现象在分子水平上尚未得到很好的理解。在这项研究中，我们进行了实验，将 CHK1 突变的受精卵的前原核转移到正常去核受精卵的细胞质中。这种方法挽救了突变引起的受精卵停滞，产生了高质量的囊胚。这表明 CHK1 功能障碍主要破坏了细胞质中发生的关键生物学过程。进一步的研究表明，CHK1 突变体对 F-肌动蛋白网格有影响，导致原核包膜破裂紊乱。通过对大约 6000 个小鼠受精卵进行免疫共沉淀和质谱分析，我们发现 CHK1 与 MICAL3 之间存在相互作用，MICAL3 是 F-肌动蛋白解体的关键调节因子。CHK1 的功能获得性突变增强了它们与 MICAL3 的相互作用，并增加了 MICAL3 的酶活性，导致 F-肌动蛋白过度解聚。这些发现揭示了哺乳动物从减数分裂到第一次有丝分裂过渡过程中原核包膜破裂的调控机制。
