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双皮质素家族激酶 ZYG-8DCLK1 调节微管动力学和马达驱动力以促进线虫无中心体纺锤体的稳定性。

The doublecortin-family kinase ZYG-8DCLK1 regulates microtubule dynamics and motor-driven forces to promote the stability of C. elegans acentrosomal spindles.

机构信息

Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.

出版信息

PLoS Genet. 2024 Sep 3;20(9):e1011373. doi: 10.1371/journal.pgen.1011373. eCollection 2024 Sep.

Abstract

Although centrosomes help organize spindles in most cell types, oocytes of most species lack these structures. During acentrosomal spindle assembly in C. elegans oocytes, microtubule minus ends are sorted outwards away from the chromosomes where they form poles, but then these outward forces must be balanced to form a stable bipolar structure. Simultaneously, microtubule dynamics must be precisely controlled to maintain spindle length and organization. How forces and dynamics are tuned to create a stable bipolar structure is poorly understood. Here, we have gained insight into this question through studies of ZYG-8, a conserved doublecortin-family kinase; the mammalian homolog of this microtubule-associated protein is upregulated in many cancers and has been implicated in cell division, but the mechanisms by which it functions are poorly understood. We found that ZYG-8 depletion from oocytes resulted in overelongated spindles with pole and midspindle defects. Importantly, experiments with monopolar spindles revealed that ZYG-8 depletion led to excess outward forces within the spindle and suggested a potential role for this protein in regulating the force-generating motor BMK-1/kinesin-5. Further, we found that ZYG-8 is also required for proper microtubule dynamics within the oocyte spindle and that kinase activity is required for its function during both meiosis and mitosis. Altogether, our findings reveal new roles for ZYG-8 in oocytes and provide insights into how acentrosomal spindles are stabilized to promote faithful meiosis.

摘要

虽然中心体有助于组织大多数细胞类型的纺锤体,但大多数物种的卵母细胞都缺乏这些结构。在 C. elegans 卵母细胞的无中心体纺锤体组装过程中,微管的负端被分拣到远离染色体的地方,在那里它们形成极,但随后这些向外的力必须平衡,以形成稳定的双极结构。同时,必须精确控制微管动力学以维持纺锤体的长度和组织。如何调整力和动力学以创建稳定的双极结构还知之甚少。在这里,我们通过对 ZYG-8 的研究获得了对此问题的深入了解;该基因编码一种保守的双皮质家族激酶;其在许多癌症中的哺乳动物同源物上调,并与细胞分裂有关,但对其作用机制知之甚少。我们发现,卵母细胞中 ZYG-8 的缺失导致纺锤体过长,极和纺锤体中部出现缺陷。重要的是,单极纺锤体实验表明,ZYG-8 的缺失导致纺锤体内向外力过剩,并表明该蛋白在调节力产生的马达 BMK-1/驱动蛋白-5 中可能发挥作用。此外,我们发现 ZYG-8 还需要卵母细胞纺锤体中的适当微管动力学,并且激酶活性对于其在减数分裂和有丝分裂中的功能都是必需的。总之,我们的发现揭示了 ZYG-8 在卵母细胞中的新作用,并提供了对无中心体纺锤体如何稳定以促进有丝分裂的深入了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b93b/11398696/d8944683f608/pgen.1011373.g001.jpg

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