Centromeres, the chromosome regions pulled by spindle fibers, weaken in aging mouse eggs, and adding a protein partially restores chromosome alignment
Centromeres, the chromosome regions pulled by spindle fibers, weaken in aging mouse eggs, and adding a protein partially restores chromosome alignment
On October 19, Journal of Cell Biology published a study from the laboratories of Binyam Mogessie (Yale University), Daniele Fachinetti (Institut Curie), and Stefanie Redemann (University of Virginia). The authors depleted most of CENP-A, the protein that forms the foundation of the centromere, in eggs from young mice. They then added CENP-C, which helps build the attachment site for spindle fibers on this foundation, to both these eggs and eggs from aging mice.
Errors during egg division leave embryos with an abnormal number of chromosomes, which accounts for nearly 35 % of miscarriages. These abnormalities become more common with age: an analysis of 15 169 embryos from IVF found that 2–6 % of patients aged 26–37 and 53 % of patients aged 44 had no embryos with a normal chromosome count. One established cause is the loss of cohesin, the protein complex that holds the copies of each chromosome together before division. However, errors rise sharply at older ages, and the authors argue that cohesin loss alone cannot explain this increase.
The centromere is where the kinetochore assembles, forming a protein structure to which spindle fibers attach. Eggs from mice aged 10–11 months contain less CENP-A and CENP-C than eggs from mice aged 8–12 weeks. Mouse eggs acquire CENP-A before birth and do not replenish it for more than a year; in women, this centromere foundation may be decades old. Whether a decline in CENP-A had functional consequences remained uncertain. In 2016, Fachinetti and colleagues removed CENP-A from human cells after DNA replication, and the centromeres remained functional during the next division: CENP-C was retained by CENP-B, a protein that binds to repetitive centromeric DNA sequences.
To test this in eggs, the authors depleted 76–84 % of CENP-A in fully grown eggs from young mice, using an antibody to mark the protein for destruction. After depletion, at least one chromosome failed to align at the spindle equator in 19 of 23 eggs (compared with 0 of 20 controls), and some chromosomes lagged during segregation in 16 of 23 eggs. The eggs completed division, and did so faster than the controls. The authors attribute this to weakening of the checkpoint that delays division until all chromosomes are attached. Cohesin levels remained unchanged, leading the authors to conclude that centromere weakening causes damage independently of cohesin loss.
CENP-C binds to CENP-A, and after CENP-A depletion, the amount of CENP-C at kinetochores fell by roughly half. Introducing mRNA encoding CENP-C into these eggs restored kinetochore CENP-C to about 65 % of normal levels and reduced the proportion of eggs with misaligned chromosomes to below 20 %. In mouse eggs lacking CENP-B and depleted of CENP-A, the added CENP-C attached poorly, and more than half of the eggs still had misaligned chromosomes. In the authors’ model, added CENP-C therefore acts through CENP-B, as in the 2016 experiment.
In naturally aged mice, chromosomes were misaligned in 39 % of eggs, compared with 12 % in young mice. Adding CENP-C reduced this proportion to 13 %, but did not change the number of lagging chromosomes, which were still uncommon.
The cytoskeleton also appears to change: three-dimensional spindle reconstructions showed that spindle fibers were less parallel in two aged eggs than in three young eggs. In 2025, Mogessie’s laboratory showed that a 30 % reduction in CENP-A, similar to that seen in aged eggs, combined with partial cohesin loss causes chromosome copies to spread farther apart than either change alone. The authors of the new study conclude:
Effective future strategies for preserving egg quality as women age will need to address centromere integrity, cytoskeletal architecture, and cohesion together, because targeting any single age-related defect will be insufficient.