与体细胞有丝分裂和种系减数分裂相关的染色体分离和细胞分裂程序显示出巨大的差异,例如动粒取向,去除cohesin,或存在间隙阶段。1,2,3,4,5,6染色体分离的这些变化需要改变已建立的细胞分裂机制。5,6尚不清楚有丝分裂和减数分裂细胞分裂之间动粒功能及其调节控制的哪些方面不同,以重新连接这些核心过程。选择性RNA剪接可以产生不同的蛋白质同种型,以允许跨细胞类型的细胞过程的差异控制。然而,差异调节不同细胞分裂程序的选择性剪接亚型仍然难以捉摸。这里,我们证明了哺乳动物生殖细胞表达动粒成分的替代性mRNA剪接同工型,DSN1,MIS12复合物的一个亚基,在染色体分离过程中连接着丝粒和纺锤体微管。这种种系DSN1同种型绕过了Aurora激酶磷酸化对其着丝粒定位的要求,因为没有关键的调节区允许DSN1显示出持续的着丝粒定位。种系DSN1同种型在体细胞中的表达导致组成型动粒定位,染色体分离错误,和生长缺陷,为其紧密的细胞类型特异性表达提供了解释。相互,在小鼠模型中精确消除种系特异性DSN1剪接同工型的表达会破坏卵母细胞成熟和早期胚胎分裂,并降低生育力。一起,这项工作确定了染色体分离成分的种系特异性剪接同工型,并暗示了其在哺乳动物生育力中的作用。
The chromosome segregation and cell division programs associated with somatic mitosis and germline meiosis display dramatic differences such as
kinetochore orientation, cohesin removal, or the presence of a gap phase.1,2,3,4,5,6 These changes in chromosome segregation require alterations to the established cell division machinery.5,6 It remains unclear what aspects of
kinetochore function and its regulatory control differ between the mitotic and meiotic cell divisions to rewire these core processes. Alternative RNA splicing can generate distinct protein isoforms to allow for the differential control of cell processes across cell types. However, alternative splice isoforms that differentially modulate distinct cell division programs have remained elusive. Here, we demonstrate that mammalian germ cells express an alternative mRNA splice isoform for the
kinetochore component, DSN1, a subunit of the MIS12 complex that links the centromeres to spindle microtubules during chromosome segregation. This germline DSN1 isoform bypasses the requirement for Aurora kinase phosphorylation for its centromere localization due to the absence of a key regulatory region allowing DSN1 to display persistent centromere localization. Expression of the germline DSN1 isoform in somatic cells results in constitutive
kinetochore localization, chromosome segregation errors, and growth defects, providing an explanation for its tight cell-type-specific expression. Reciprocally, precisely eliminating expression of the germline-specific DSN1 splice isoform in mouse models disrupts oocyte maturation and early embryonic divisions coupled with a reduction in fertility. Together, this work identifies a germline-specific splice isoform for a chromosome segregation component and implicates its role in mammalian fertility.