The high rate of aneuploidy in human eggs could be explained by an unusually long meiotic spindle assembly period which favors chromosome segregation errors, according to a new study published in Science.
Dr. Zuzana Holubcova and her colleagues established an experimental system for ex vivo high-resolution fluorescence microscopy of human oocytes that allowed them to observe the major stages of meiosis in the laboratory.
Human oocyte spindle assembly was controlled primarily by chromosomes and the small guanosine triphosphatase Ran and was independent of centrosomes or other microtubule organization. This process took about 16 hours to complete, considerably longer than 30 minutes needed for spindle assembly in cells undergoing mitosis or the 3-5 hours required for mouse oocyte meiosis.
While nearly all oocytes progressed into anaphase with bipolar spindles, over the course of spindle assembly, 44% of spindles showed moderate instability with an apolar phase, and 38% of spindles showed severe instability with a multipolar phase. Oocytes with abnormal spindles were more likely to have persistent lagging chromosomes during anaphase, which were associated with abnormal kinetochore-microtubule attachments.
“Spindle instability may reflect attempts of the chromosomes to establish stable bipolar microtubule attachments, which could be more challenging in human oocytes, possibly due to structural features of their chromosomes abnormal attachments,” the researchers wrote. “Progression into anaphase with these abnormal attachments would put the oocyte at risk of chromosome segregation errors, providing at least one mechanism for the relatively frequent aneuploidy of eggs, even in young women.”
Find the full study in Science (doi: 10.1126/science.aaa9529).
Watch a video of spindle assembly here.
This video shows 3D volume reconstructions of kinetochores, chromosomes, and microtubules in cold-treated human oocytes fixed during early (left) or late (right) spindle assembly.
Credit: Zuzana Holubcova and Melina Schuh, MRC Laboratory of Molecular Biology