Age‐dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B

Abstract

A hallmark of advanced maternal age is a significant increase in meiotic chromosome segregation errors, resulting in early miscarriages and congenital disorders. These errors most frequently occur during meiosis I (MI). The spindle assembly checkpoint (SAC) prevents chromosome segregation errors by arresting the cell cycle until proper chromosome alignment is achieved. Unlike in mitosis, the SAC in oocytes is desensitized, allowing chromosome segregation in the presence of improperly aligned chromosomes. Whether SAC integrity further deteriorates with advancing maternal age, and if this decline contributes to increased segregation errors remains a fundamental question. In somatic cells, activation of the SAC depends upon Aurora kinase B (AURKB), which functions to monitor kinetochore–microtubule attachments and recruit SAC regulator proteins. In mice, oocyte‐specific deletion of AURKB (Aurkb cKO) results in an increased production of aneuploid metaphase II‐arrested eggs and premature age‐related infertility. Here, we aimed to understand the cause of the short reproductive lifespan and hypothesized that SAC integrity was compromised. In comparing oocytes from young and sexually mature Aurkb cKO females, we found that SAC integrity becomes compromised rapidly with maternal age. We show that the increased desensitization of the SAC is driven by reduced expression of MAD2, ZW10 and Securin proteins, key contributors to the SAC response pathway. The reduced expression of these proteins is the result of altered protein homeostasis, likely caused by the accumulation of reactive oxygen species. Taken together, our results demonstrate a novel function for AURKB in preserving the female reproductive lifespan possibly by protecting oocytes from oxidative stress.

Insufficient HtrA2 causes meiotic defects by inducing cytoskeletal disorganization in aging germinal vesicle oocytes

“…The SAC is desensitized during oocyte meiosis, permitting chromosomal segregation in the presence of several chromosomal misarrangements [27]. Even though the SAC was induced during meiosis, almost 44% of HtrA2-KD oocytes extruded the rst polar body (Fig.…”

“…Given that decreased HtrA2 expression impeded extrusion of the rst polar body, we hypothesized that HtrA2 might be involved in spindle organization or migration during meiosis. During this process, the SAC acts as a safety mechanism, which holds the oocyte in the metaphase-to-anaphase transition of meiotic phase I until all chromosomes are aligned and microtubules have been correctly attached [27]. Given the arrest in MI of HtrA2-KD young oocytes, we hypothesized potential activation of the SAC.…”

Chromosome Segregation in the Oocyte: What Goes Wrong during Aging

“…The SAC is triggered by unattached kinetochores. In a recent study on mice oocytes, it was revealed that AURKB appears to play a role in the maintenance of the female reproductive lifespan, most likely because of its defensive property against the excessive accumulation of reactive oxygen species in the egg [ 51 ]. However, this is only one possible factor among others.…”

“…However, this is only one possible factor among others. Therefore, further investigations on the abundance of AURKB with respect to the advancing age of the egg could shed light on its ability to be used as an adequate biomarker for oocyte developmental competence in women with aging-related decreases in fertility [ 51 ].…”

Using ZINC08918027 inhibitor to determine Aurora kinase-chromosomal passenger complex isoforms in mouse oocytes

“…AURKC is responsible for most functions that AURKB-CPC has in mitosis [ 8 , 9 ], including regulating chromosome alignment and correcting erroneous kinetochore-microtubule attachments [ 10 – 12 ]. As a result, AURKB is diffuse in the oocyte cytoplasm and has still to be defined mechanisms in protecting egg quality with age [ 13 , 14 ]. Therefore, subcellular localization and function of AURKA and AURKC in mouse oocytes is dictated by their binding to different activators as in mitotic cells.…”