NEK2 通过 Wnt/β-catenin 信号通路维持有丝分裂和 DNA 损伤反应，在猪胚胎发育中发挥重要作用,Cell Proliferation

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NEK2 通过 Wnt/β-catenin 信号通路维持有丝分裂和 DNA 损伤反应，在猪胚胎发育中发挥重要作用
Cell Proliferation ( IF 5.9 ) Pub Date : 2024-03-01 , DOI: 10.1111/cpr.13626
Se‐Been Jeon _{1,

2} , Pil‐Soo Jeong ₁ , Hyo‐Gu Kang _{1,

3} , Min Ju Kim _{1,

2} , Ji Hyeon Yun _{1,

4} , Kyung Seob Lim ₁ , Bong‐Seok Song ₁ , Sun‐Uk Kim _{1,

5} , Seong‐Keun Cho ₆ , Bo‐Woong Sim ₁

Affiliation

NIMA 相关激酶 2 (NEK2) 是一种丝氨酸/苏氨酸蛋白激酶，可调节有丝分裂，在细胞周期调节和 DNA 损伤修复中发挥关键作用。然而，其在猪胚胎发育中的功能尚不清楚。在本研究中，我们使用 NEK2 特异性抑制剂 JH295 (JH) 来研究 NEK2 在胚胎发育中的作用及其潜在的调控机制。与对照条件相比，单性生殖激活或体外受精后抑制NEK2显着降低卵裂和囊胚形成率、滋养外胚层和总细胞的数量以及细胞存活率。NEK2 抑制延迟了第一次有丝分裂期间从间期到胞质分裂的所有阶段的细胞周期进展；它导致双细胞和四细胞阶段胚胎的核形态异常。此外，NEK2 抑制显着增加 DNA 损伤和细胞凋亡，并改变 DNA 损伤修复和细胞凋亡相关基因的表达水平。有趣的是，NEK2 抑制下调了 β-catenin 及其下游靶基因的表达。为了验证猪胚胎发育过程中 Wnt/β-catenin 信号传导与 NEK2 之间的关系，我们在含有或不含 CHIR99021（一种 Wnt 激活剂）的 JH 处理培养基中培养猪胚胎。CHIR99021 联合治疗强烈地将 NEK2 抑制降低的发育参数恢复到对照水平。我们的研究结果表明，NEK2 通过 Wnt/β-catenin 信号通路调节 DNA 损伤修复和正常有丝分裂，在猪胚胎发育中发挥重要作用。

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NEK2 plays an essential role in porcine embryonic development by maintaining mitotic division and DNA damage response via the Wnt/β‐catenin signalling pathway

NIMA‐related kinase 2 (NEK2) is a serine/threonine protein kinase that regulates mitosis and plays pivotal roles in cell cycle regulation and DNA damage repair. However, its function in porcine embryonic development is unknown. In this study, we used an NEK2‐specific inhibitor, JH295 (JH), to investigate the role of NEK2 in embryonic development and the underlying regulatory mechanisms. Inhibition of NEK2 after parthenogenesis activation or in vitro fertilization significantly reduced the rates of cleavage and blastocyst formation, the numbers of trophectoderm and total cells and the cellular survival rate compared with the control condition. NEK2 inhibition delayed cell cycle progression at all stages from interphase to cytokinesis during the first mitotic division; it caused abnormal nuclear morphology in two‐ and four‐cell stage embryos. Additionally, NEK2 inhibition significantly increased DNA damage and apoptosis, and it altered the expression levels of DNA damage repair‐ and apoptosis‐related genes. Intriguingly, NEK2 inhibition downregulated the expression of β‐catenin and its downstream target genes. To validate the relationship between Wnt/β‐catenin signalling and NEK2 during porcine embryonic development, we cultured porcine embryos in JH‐treated medium with or without CHIR99021, a Wnt activator. CHIR99021 co‐treatment strongly restored the developmental parameters reduced by NEK2 inhibition to control levels. Our findings suggest that NEK2 plays an essential role in porcine embryonic development by regulating DNA damage repair and normal mitotic division via the Wnt/β‐catenin signalling pathway.

更新日期：2024-03-01

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