Date of Award
12-2024
Document Type
Open Access Thesis
Degree Name
Doctor of Philosophy (PhD)
Department
Biology/Molecular, Cellular, and Organismal Biology
First Advisor
Kellee Siegfried
Second Advisor
Linda Huang
Third Advisor
Catherine McCusker, Shailja Pathania, Monica Colaiacovo
Abstract
Infertility is a growing problem worldwide. According to the WHO, 48 million couples across the globe suffer from infertility and many couples turn to Assisted Reproductive Technology (ART) to become pregnant. One readout of gamete quality and successful ART is telomere integrity because telomeres are necessary for chromosome movements during meiosis so that the segregation of chromosomes happens correctly. Telomeres are well known for their role in aging; however, they play an important and understudied role during meiosis. In meiosis, telomeres attach to the nuclear envelope (NE) via a protein chain spanning the NE that interacts with cytoplasmic motor proteins, which are called nuclear envelope adaptor protein complexes. Through this interaction, chromosomes are shuffled within the nucleus to facilitate homologous chromosome pairing. If this process does not proceed normally, aneuploid gametes may be produced leading to infertility or congenital defects in offspring. My dissertation work focused on understanding how proper telomere length is necessary for meiosis and identifying the meiotic nuclear envelope adaptor protein complex in zebrafish. Through studying the necessity of telomere length using telomerase reverse transcriptase (tert) mutant zebrafish, I aim to tease apart the functions of telomeres during gamete development. The tert mutant phenotype includes decreased telomere length, aberrant germ cell development, and infertility. I hypothesize that the germ cell defects are in part due to problems in meiosis resulting from the shortened telomeres. My work found that the meiotic cells in the testis are more sensitive to telomere shortening than non-meiotic germ cells. By analyzing germ cells undergoing meiosis at both 3 months of age and 5 months, I found an increase of mutant spermatocytes in the leptotene stage of meiotic prophase I, which is when telomeres attach to the NE, suggesting that telomeres of appropriate length are required for meiotic progression. I also found there to be an increase in š¯›¾-H2ax staining in mutant pachytene cells, at both ages, suggesting problems in resolving DSBs that are necessary for homologous recombination. Taken together, these defects suggest that telomeres of a proper length are needed for successful meiosis in zebrafish. Additionally, I investigated the potential role of the genes terb1, terb2, and majin as encoding for the zebrafish meiotic nuclear envelope adaptor protein complex given that they function in this way in mammals. All three genes are expressed in zebrafish gonads and terb1 was found to be necessary for fertility and meiosis in zebrafish, reflecting its putative role as part of the machinery linking the telomeres and microtubules of the cell during meiosis. My work has shown the importance proper telomere length has not only on aging, but on meiosis and fertility, a growing problem worldwide.
Recommended Citation
MacNeil, Jessica, "Size Matters: The Characterization of Telomere Function in Germ Cell Development in Danio Rerio" (2024). Graduate Doctoral Dissertations. 1025.
https://scholarworks.umb.edu/doctoral_dissertations/1025
Comments
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