Zwint-1 is required for spindle assembly checkpoint function and kinetochore-microtubule attachment during oocyte meiosis.

Dong Woo Seo,Woo-Jae Chung,Dong-Hyung Cho,Jae-Sung Kim,Seung Yeop You,Jeong Su Oh

doi:10.1038/srep15431

Abstract

The key step for faithful chromosome segregation during meiosis is kinetochore assembly. Defects in this process result in aneuploidy, leading to miscarriages, infertility and various birth defects. However, the roles of kinetochores in homologous chromosome segregation during meiosis are ill-defined. Here we found that Zwint-1 is required for homologous chromosome segregation during meiosis. Knockdown of Zwint-1 accelerated the first meiosis by abrogating the kinetochore recruitment of Mad2, leading to chromosome misalignment and a high incidence of aneuploidy. Although Zwint-1 knockdown did not affect Aurora C kinase activity, the meiotic defects following Zwint-1 knockdown were similar to those observed with ZM447439 treatment. Importantly, the chromosome misalignment following Aurora C kinase inhibition was not restored after removing the inhibitor in Zwint-1-knockdown oocytes, whereas the defect was rescued after the inhibitor washout in the control oocytes. These results suggest that Aurora C kinase-mediated correction of erroneous kinetochore-microtubule attachment is primarily regulated by Zwint-1. Our results provide the first evidence that Zwint-1 is required to correct erroneous kinetochore-microtubule attachment and regulate spindle checkpoint function during meiosis.

Highlights

Of the KMN network are largely dependent on Aurora B kinase, a component of the chromosome passenger complex (CPC)[11]
We found that Zwint-1 is required for Aurora C kinase to correct erroneous kMT attachment and to activate the SAC at unattached kinetochores, thereby ensuring faithful segregation of homologous chromosomes during oocyte meiosis
Zwint-1-knockdown oocytes underwent polar body extrusion (PBE), with no significant differences observed between control and knockdown oocytes (Fig. 1c)

Summary

Introduction

Of the KMN network are largely dependent on Aurora B kinase (in meiotic cells, Aurora C kinase functions in parallel with or substitutes for Aurora B kinase7–10), a component of the chromosome passenger complex (CPC)[11]. Zwint-1 was shown to be phosphorylated by Aurora B kinase; this phosphorylation is required for the recruitment of the RZZ complex, which is in turn a prerequisite for the recruitment of SAC proteins[16]. Zwint-1 appears to bridge the KMN network with the RZZ complex. This KMN-Zwint-1-RZZ connection enables signals to be properly transferred from Aurora B kinase, the main regulator of kinetochore assembly, to the SAC. We investigated the function of the kinetochore protein Zwint-1 in oocyte meiotic maturation. We found that Zwint-1 is required for Aurora C kinase to correct erroneous kMT attachment and to activate the SAC at unattached kinetochores, thereby ensuring faithful segregation of homologous chromosomes during oocyte meiosis

Methods

Results

Conclusion