Initial spindle positioning at the oocyte center protects against incorrect kinetochore-microtubule attachment and aneuploidy in mice

Abstract

Spindle positioning within the oocyte must be tightly regulated. In mice, the spindle is predominantly assembled at the oocyte center before its migration toward the cortex to achieve the highly asymmetric division, a characteristic of female meiosis. The significance of the initial central positioning of the spindle is largely unknown. We show that initial spindle positioning at the oocyte center is an insurance mechanism to avoid the premature exposure of the spindle to cortical CDC42 signaling, which perturbs proper kinetochore-microtubule attachments, leading to the formation of aneuploid gametes. These findings contribute to understanding why female gametes are notoriously associated with high rates of aneuploidy, the leading genetic cause of miscarriage and congenital abnormalities.

Sirtuin 5-driven meiotic spindle assembly and actin-based migration in mouse oocyte meiosis

“…Precise spindle assembly is pivotal for the correct segregation of chromosomes in meiosis and the generation of healthy oocytes [ 16 ]. Errors at any stage of spindle assembly and chromosomal alignment can lead to the production of aneuploid oocytes, which in turn may result in aneuploid embryos, causing embryo implantation failure and early pregnancy loss [ 8 , 9 ].…”

“…It requires the cytoskeleton, chromosomes, and an array of proteins to coordinate precisely within the oocyte to ensure accurate regulation [ 14 ]. The migration and positioning of the meiotic spindle at the cortex of the oocyte are crucial for asymmetric division, with actin microfilaments assuming a vital role in spindle migration [ 15 , 16 ]. As the meiotic spindle forms near the center of the cell, actin microfilaments accumulate around the periphery of the spindle and form actin flows, which facilitate spindle migration from the center to the cortex [ 17 ].…”

Mevalonate metabolites boost aged oocyte quality through small GTPases prenylation

“…CDC42 and RAC1 are members of the Rho GTPases family, a small guanosine triphosphatase (GTPase) subfamily of proteins that oscillate between the GTPbound (active) and GDP-bound (inactive) states 39 . CDC42 and RAC1 are enriched at the cortex after spindle migration and cortical F-actin assembly are necessary for the extrusion of the rst polar body during oocyte meiosis [40][41][42][43][44][45] . We con rmed that CDC42 and RAC1 have CaaX motifs at the carboxyl terminus and can be prenylated by FPP in oocytes.…”