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Dissertation
CHTF18 Safeguards the Quantity and Quality of the Ovarian Reserve and Mediates Meiotic Cohesion
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2023
DOI:
https://doi.org/10.17918/00001580
Abstract
As women age, a decline in oocyte quality due to aneuploidy leads to infertility, miscarriage, and congenital anomalies. Age-related aneuploidy can arise from meiotic errors and loss of chromosome cohesion, the defects of which are incompletely understood. In these studies, we report that CHTF18, a subunit of the Replication Factor C-Like complex, ensures the quality and quantity of the oocyte pool and mediates female meiotic cohesion via cohesins. Chtf18-/- female mice display age-dependent subfertility and ovaries that contain significantly fewer follicles than wild-type females. Consistent with age-dependent subfertility, Chtf18-/- follicle pools are nearly depleted by six months of age, and female neonates are born with fewer follicles than wild-type controls. In Chtf18-/- oocytes, homologous chromosomes undergo synapsis but separate prematurely during prophase I. Meiotic recombination is also defective with persistent DNA double-strand breaks and decreased crossovers. Consequently, Chtf18-/- oocytes are poor quality and fail to progress or are aneuploid at metaphase II. Interestingly, centromeric cohesion is also weakened in Chtf18-/- oocytes at metaphase II. Given the phenotypes of premature homolog disjunction and weakened centromeric cohesion in Chtf18-/-oocytes, we investigated a role for CHTF18 in meiotic cohesion. We revealed that chromosome-associated REC8, a meiotic cohesin, is decreased in prophase I and metaphase I oocytes, suggesting that CHTF18 aids in stabilizing and maintaining REC8 on chromatin during meiosis I. Because cohesins function via regulator proteins, we assessed NIPBL, PDS5B, and WAPL, involved in cohesin loading, maintenance, and release. In Chtf18-/- oocytes PDS5B was significantly decreased and WAPL was mislocalized during prophase I. These results suggest that CHTF18 interacts with PDS5B and/or WAPL, which may facilitate REC8 association with chromatin during meiosis. CHTF18 is known to play a role in cohesion establishment during mitosis. Therefore, we postulate a crucial role for CHTF18 in cohesion establishment and maintenance during female meiosis. By defining the role of CHTF18 in female meiotic cohesion, we aim to better understand how the age-related decline in oocyte quality arises, ultimately leading to improved infertility treatments in women.
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Details
- Title
- CHTF18 Safeguards the Quantity and Quality of the Ovarian Reserve and Mediates Meiotic Cohesion
- Creators
- Rebecca Anne Holton
- Contributors
- Karen M. Berkowitz (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 141 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991020503314804721