去泛素化酶USP21在纺锤体定向调控中的作用及分子机制

纺锤体是有丝分裂过程中关键的细胞器，对遗传物质的精确分离及细胞命运的决定十分重要。纺锤体发挥功能依赖于它相对于细胞皮层的精确旋转，即纺锤体定向。纺锤体定向在胚胎发育、组织器官形成及损伤组织的修复过程中起关键作用。纺锤体定向错误会导致发育异常及肿瘤等疾病的发生。然而到目前为止，纺锤体定向的调控机制尚不清楚。本项目前期的研究显示，去泛素化酶USP21能够调节纺锤体定向。Usp21敲除小鼠出现肾小管上皮细胞纺锤体定向异常且肾小管直径增大的缺陷。在此基础上，本项目将深度分析USP21在纺锤体定向调控中的功能，鉴定与USP21相互作用的蛋白质分子，进而解析USP21调节纺锤体定向的分子机制，并初步揭示USP21对纺锤体定向的调控在肾小管发育中的功能。此项目的顺利完成将揭示纺锤体定向调控的新机制，并为我们探究纺锤体定向错误引起的发育疾病提供理论基础。

The spindle apparatus, a crucial organelle during mitosis, is essential for proper chromosome segregation and cell fate choices. The function of mitotic spindle in cell division relies on its accurate orientation relative to the cell cortex, namely spindle orientation. Spindle orientation is essential for embryogenesis, organ and tissue morphogenesis as well as wound repair. Emerging evidence shows that improper spindle orientation could result in developmental diseases as well as tumor formation. However, the molecular mechanisms underlying the regulation of spindle orientation remain unknown. In our previous studies, we identified a previously unrecognized role for ubiquitin-specific protease 21 (USP21) in the control of spindle orientation. We found that the mitotic spindle angel of dividing renal tubular epithelial cells is incorrect and the tubule diameter increases in USP21-deficient mice. In the proposed study, we will dissect deeply the functions of USP21 in spindle orientation, identify the proteins interacting with USP21,reveal the molecular mechanisms of action of USP21 and explore how this signaling pathway influence renal tubular development. Upon successful conclusion of these studies, we will provide novel insights into the signaling network which participates in spindle orientation and provide theoretical basis for exploring developmental diseases induced by spindle misorientation.