Mechanisms underlying age-related decline in mammalian female fertility
von Ninadini Sharma
Datum der mündl. Prüfung:2023-01-25
Erschienen:2024-03-05
Betreuer:Dr. Melina Schuh
Gutachter:Prof. Dr. Matthias Dobbelstein
Gutachter:Dr. Alex Caspar Faesen
Gutachter:Dr. Peter Lenart
Gutachter:Prof. Dr. Markus Bohnsack
Gutachter:Prof. Dr. Rüdiger Behr
Dateien
Name:Ninadini_Sharma_PhD_Thesis_without_CV.pdf
Size:135.Mb
Format:PDF
Diese Datei ist bis 24.01.2025 gesperrt.
Zusammenfassung
Englisch
Reproductive longevity is crucial for fertility and impacts healthy ageing. Unlike in men, fertility in women starts to decline several decades before other signs of ageing set in. Female fertility is restricted by a limited supply of oocytes established at birth. Loss of oocyte quantity and quality occurs progressively from birth and is accelerated as women approach their mid-30s. The DNA damage response is one of the primary pathways believed to drive oocyte loss. Elevated levels of DNA double-strand breaks (DSBs) can trigger oocyte death, and thus contribute to the loss of female fertility with age. Although we know that oocytes can repair DNA damage, how and why DNA damage accumulates with ageing is poorly understood. This thesis identifies changes in DNA repair maternal ageing that contribute to loss of female fertility.Maternal ageing is also accompanied by a high frequency of chromosome segregation errors during meiosis in oocytes that can lead to aneuploidy. In the second part of my thesis, I developed high-resolution imaging and tracking methods to identify the origin of chromosome segregation errors, as well as their fate and contribution towards aneuploidy. Taken together, the work presented in the thesis unveils new causes of the age-related decline in female fertility and paves the way towards further studies into chromosome segregation dynamics that lead to aneuploidy in human oocytes.
Keywords: oocyte; meiosis; fertility; aging; DNA damage; DNA repair; cohesin