Yu Wen-Xin, Li Yu-Kun, Xu Meng-Fei, Xu Chen-Jie, Chen Jie, Wei Ya-Lan, She Zhen-Yu
Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, 350122, Fuzhou, Fujian, China.
Key Laboratory of Stem Cell Engineering and Regenerative Medicine, Fujian Province University, 350122, Fuzhou, Fujian, China.
Cell Death Discov. 2022 Dec 13;8(1):490. doi: 10.1038/s41420-022-01281-1.
Chromosome stability relies on bipolar spindle assembly and faithful chromosome segregation during cell division. Kinesin-5 Eg5 is a plus-end-directed kinesin motor protein, which is essential for spindle pole separation and chromosome alignment in mitosis. Heterozygous Eg5 mutations cause autosomal-dominant microcephaly, primary lymphedema, and chorioretinal dysplasia syndrome in humans. However, the developmental roles and cellular mechanisms of Eg5 in organogenesis remain largely unknown. In this study, we have shown that Eg5 inhibition leads to the formation of the monopolar spindle, chromosome misalignment, polyploidy, and subsequent apoptosis. Strikingly, long-term inhibition of Eg5 stimulates the immune responses and the accumulation of lymphocytes in the mouse spleen through the innate and specific immunity pathways. Eg5 inhibition results in metaphase arrest and cell growth inhibition, and suppresses the formation of somite and retinal development in zebrafish embryos. Our data have revealed the essential roles of kinesin-5 Eg5 involved in cell proliferation, chromosome stability, and organogenesis during development. Our findings shed a light on the cellular basis and pathogenesis in microcephaly, primary lymphedema, and chorioretinal dysplasia syndrome of Eg5-mutation-positive patients.
染色体稳定性依赖于细胞分裂过程中的双极纺锤体组装和准确的染色体分离。驱动蛋白-5 Eg5是一种向正极移动的驱动蛋白运动蛋白，对有丝分裂过程中的纺锤体极分离和染色体排列至关重要。杂合的Eg5突变会导致人类常染色体显性小头畸形、原发性淋巴水肿和脉络膜视网膜发育异常综合征。然而，Eg5在器官发生中的发育作用和细胞机制仍 largely未知。在本研究中，我们表明Eg5抑制会导致单极纺锤体形成、染色体排列错误、多倍体形成以及随后的细胞凋亡。引人注目的是，长期抑制Eg5会通过先天免疫和特异性免疫途径刺激小鼠脾脏中的免疫反应和淋巴细胞积累。Eg5抑制导致中期停滞和细胞生长抑制，并抑制斑马鱼胚胎中体节的形成和视网膜发育。我们的数据揭示了驱动蛋白-5 Eg5在发育过程中参与细胞增殖、染色体稳定性和器官发生的重要作用。我们的发现为Eg5突变阳性患者的小头畸形、原发性淋巴水肿和脉络膜视网膜发育异常综合征的细胞基础和发病机制提供了线索。
