Abstract
Human and mouse oocytes’ developmental potential can be predicted by their mechanical properties. Their development into blastocysts requires a specific stiffness window. In this study, we combine live-cell and computational imaging, laser ablation, and biophysical measurements to investigate how deregulation of cortex tension in the oocyte contributes to early developmental failure. We focus on extra-soft cells, the most common defect in a natural population. Using two independent tools to artificially decrease cortical tension, we show that chromosome alignment is impaired in extra-soft mouse oocytes, despite normal spindle morphogenesis and dynamics, inducing aneuploidy. The main cause is a cytoplasmic increase in myosin-II activity that could sterically hinder chromosome capture. We describe here an original mode of generation of aneuploidies that could be very common in oocytes and could contribute to the high aneuploidy rate observed during female meiosis, a leading cause of infertility and congenital disorders.
Highlights
Human and mouse oocytes’ developmental potential can be predicted by their mechanical properties
Whereas chromosomes are aligned on the metaphase I plate in controls, cortical verprolin-homology coflilin-homology acidic (cVCA) oocytes display chromosome alignment defects before anaphase I (Fig. 1b)
In cVCA oocytes, aspect ratios formed a bimodal distribution between 0 and 1, arguing that some of the oocytes displayed chromosomes that were aligned as in the controls but others displayed chromosomes that were misaligned (Fig. 1d blue curve bars). This computational approach allowed us to quantify and validate the chromosome alignment defect we observed in cVCA oocytes, and allowed us to find an easy criterion to measure it in an unbiased manner (Fig. 1d)
Summary
Human and mouse oocytes’ developmental potential can be predicted by their mechanical properties. Using two independent tools to artificially decrease cortical tension, we show that chromosome alignment is impaired in extra-soft mouse oocytes, despite normal spindle morphogenesis and dynamics, inducing aneuploidy. We show that expression of this construct induces myosin-II cortical displacement and reduces cortical tension Using these two approaches, we observe impaired chromosome alignment and aneuploidy in extra-soft oocytes, despite normal spindle assembly and dynamics as assessed by MT density and growth measurements. A cytoplasmic increase in myosin-II activity appears as the main cause of chromosome misalignment, potentially sterically hindering chromosome capture, as decreasing myosin-II activity in extra-soft oocytes rescues alignment. A fraction of these naturally soft oocytes might present chromosome alignment defects impeding on their future development after fertilization, contributing to the high aneuploidy rate measured in female meiosis, a leading cause of infertility[1]
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