Mechanisms of spindle pole organization and instability in human oocytes

Chromosomal errors in human eggs are a major cause of miscarriage and infertility

These errors are caused by chromosomal mismatches during oocyte maturation into eggs

Aneuploidy of human eggs is a major cause of abnormal embryonic development, leading to pregnancy loss and genetic disorders such as Down syndrome

We therefore set out to investigate how the spindle poles are organized in the absence of centrosomes and why the spindle is unstable in human oocytes

We found that the microtubule cross-linking protein NUMA (mitogen) localizes to the minus end of microtubules, where it recruits the molecular motor dynein for spindle pole focusing

We therefore asked whether spindle instability is a common feature of mammalian oocytes that use NUMA for spindle pole organization

Mammalian oocyte spindle and oocyte spindle loss are increased, resulting in oocyte spindle instability

In somatic cells, two centrosomes serve as the main MTOCs, facilitating the assembly of the bipolar spindle

Stabilize the poles and spindle

Thus, our data also reveal a potential approach to improve the fidelity of spindle assembly and chromosome segregation in human oocytes

Deletion of the molecular motor KIFC1 in aMTOC-free mouse oocytes (left) and bovine oocytes (middle) results in missegregation of multipolar spindles (grey) and chromosomes (magenta), reproducing human oocytes (right) spindle instability, as shown in these immunofluorescence images

In contrast, introduction of exogenous KIFC1 stabilized spindles in human oocytes that are naturally deficient in KIFC1

Summary

Human oocytes are prone to form extremely unstable meiotic spindles, which are favorable for egg cell aneuploidy

The root cause of spindle instability is not known