Age-associated increase in aneuploidy and changes in gene expression in mouse eggs

Area of Science:

• Reproductive Biology
• Genetics
• Molecular Biology

Background:

• Aneuploidy, an abnormal chromosome number, increases with maternal age, impacting human fertility.
• The molecular mechanisms underlying age-related aneuploidy remain poorly understood.

Purpose of the Study:

• To investigate the molecular basis of age-associated aneuploidy in female reproduction using a mouse model.
• To identify molecular changes in oocytes and eggs from aged females that contribute to aneuploidy and reduced fertility.

Main Methods:

• Comparative analysis of chromosome spreads in eggs from young and old mice.
• Transcriptome expression profiling of oocytes and eggs from young (6-12 weeks) and old (60-70 weeks) mice.
• RNA interference (RNAi) to assess the role of BRCA1 in oocyte maturation and chromosome segregation.

Main Results:

• A 6-fold increase in hyperploidy was observed in eggs from old mice.
• Significant alterations in maternal mRNA degradation patterns during oocyte maturation in aged mice, with ~5% of transcripts differentially expressed in oocytes and ~33% in eggs.
• Weakened spindle assembly checkpoint and increased microtubule-kinetochore interaction errors were identified.
• Reduced BRCA1 expression in oocytes from old mice; RNAi-mediated BRCA1 reduction in young oocytes disrupted spindle formation and chromosome congression.

Conclusions:

• Age-associated changes in maternal mRNA regulation and compromised spindle assembly checkpoint contribute to aneuploidy in aged female mice.
• Reduced BRCA1 expression is implicated in age-related errors in oocyte maturation and chromosome segregation, potentially explaining decreased fertility.