Segregating Chromosomes in the Mammalian Oocyte

Abstract

Chromosome segregation errors in human oocytes lead to aneuploid embryos that cause infertility and birth defects. Here we provide an overview of the chromosome-segregation process in the mammalian oocyte, highlighting mechanistic differences between oocytes and somatic cells that render oocytes so prone to segregation error. These differences include the extremely large size of the oocyte cytoplasm, the unique geometry of meiosis-I chromosomes, idiosyncratic function of the spindle assembly checkpoint, and dramatically altered oocyte cell-cycle control and spindle assembly, as compared to typical somatic cells. We summarise recent work suggesting that aging leads to a further deterioration in fidelity of chromosome segregation by impacting multiple components of the chromosome-segregation machinery. In addition, we compare and contrast recent results from mouse and human oocytes, which exhibit overlapping defects to differing extents. We conclude that the striking propensity of the oocyte to mis-segregate chromosomes reflects the unique challenges faced by the spindle in a highly unusual cellular environment.

Human oocytes harbouring damaged dna can complete meiosis-i

“…Our monastrol data ( Figure 6) provides a simple but clear indication that severe loss of spindle organisation can activate SAC and prevent polar body extrusion. Therefore taken together with the aforementioned work, it would appear that in human oocytes as in mouse, aspects of the pathway are functional, but SAC is insensitive to prevent segregation errors, providing at least part of the explanation for the high levels of aneuploidy in the human oocyte (Gui and Homer, 2012;Hassold and Hunt, 2001;Mihajlović and FitzHarris, 2018).…”

“…The function of the spindle checkpoint in mammalian oocytes has long been a source of contention. In mouse, whereas severe spindle disruption activates the checkpoint to prevent polar body extrusion, moderate spindle insults fail to prevent polar body extrusion, causing defective chromosome segregation that likely leads to aneuploidy (discussed in (Greaney et al, 2017;Mihajlović and FitzHarris, 2018)). But little has been known about the spindle checkpoint in human oocytes.…”

“…Any unattached kinetochore triggers the formation of an inhibitory signal that prevents anaphase until correct attachment has been attained (Lara-Gonzalez et al, 2012;Musacchio, 2015). However, it has long been realised that the SAC is highly ineffective at preventing aneuploidy in the mammalian oocyte (Greaney et al, 2017;Mihajlović and FitzHarris, 2018). SAC signalling is evidently in operation in the mouse oocyte, since extreme spindle damage can prevent polar body formation, and removal of SAC components shortens meiosis and exacerbates chromosome segregation errors (Homer et al, 2005;McGuinness et al, 2009).…”

“…However, importantly, interventions that cause moderate spindle defects fail to elicit a SAC-mediated meiosis-I arrest, and oocytes can initiate anaphase chromosome segregation during oocyte maturation despite misaligned chromosomes that could cause aneuploidy (Gui and Homer, 2012;Kolano et al, 2012;Lane et al, 2012;Sebestova et al, 2012). Thus, at least in mouse, the SAC is unusually ineffective at detecting spindle defects in the oocyte (reviewed in (Mihajlović and FitzHarris, 2018)).…”

WOMEN IN REPRODUCTIVE SCIENCE: Errors and insight: intentional and accidental studies of human chromosome abnormalities

“…It suggested the high error rate in oocytes was not simply a matter of making more mistakes but of allowing cells to survive and become viable eggs -albeit ones that would give rise to aneuploid embryos. I assumed this cell cycle control difference would become the focus of my research, but serendipitous events turned our efforts in another direction, while others unraveled the unique features of the mammalian oocyte that allow cells with errors in chromosome attachment and alignment to become viable gametes (Homer et al 2005, McGuinness et al 2009, Kolano et al 2012, Mihajlovic & FitzHarris 2018.…”