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theses

Infertility is a condition that impacts 1 in 6 couples worldwide and is defined as the inability to get pregnant, or stay pregnant, after 1 year of trying to conceive. The causes of infertility are vast, and can stem from either the paternal and maternal side or a combination of the two. One common source of infertility is the presence of an abnormal number of chromosomes (aneuploidy) in the developing egg or sperm. Aneuploidies are frequently incompatible with life, and in humans are the major genetic contributor to miscarriage, infertility, developmental disabilities, and failure of in vitro fertilization. While rare in most organisms, humans are particularly prone to chromosomal abnormalities, with 10–30% of fertilized eggs being aneuploid, accounting for nearly one third of miscarriages. This is in stark contrast to only 1-2% of sperm being aneuploid. Aneuploidy in eggs most often arises due to errors in the first meiotic division, accounting for greater than 56% of all occurrences in both male and female meiosis. The Aurora kinases are a family of serine/threonine kinases critical to regulating chromosome segregation and preventing aneuploidy in both mitosis and meiosis. While the functions of these proteins in mitosis are well understood, their function, regulation, and localization in meiosis remains unclear. Here we sought to understand the distinct functions of the three Aurora kinases expressed in female meiosis; Aurora A, Aurora B, and Aurora C. We show that Aurora C localization is regulated via the phosphorylation of Histone 3 at Threonine 3 by Haspin kinase, and this localization is imperative for the correction of aberrant kinetochore-microtubule attachments and mitigating chromatid condensation. Utilizing a meiosis specific Cre-lox system we show for the first time the requirement for Aurora kinase B in mouse oocytes and a specific function in regulating meiotic cohesion. Next we discover the presence of a negative regulatory network among the Aurora kinases, with Aurora C uniquely required to restrict Aurora A to spindle poles while Aurora B is required to restrict Aurora C activity. Failure for any of these kinases to function properly can lead to meiotic arrest, small spindle structures, chromosomal alignment defects, the premature separation of sister chromatids, and ultimately meiotic aneuploidy. Finally, we identified the presence of a human variant in the Aurora kinases that may be protective of gamete euploidy. Understanding how the Aurora kinases regulate meiosis is critical to our understanding of this unique cell cycle and correspondingly, how errors in meiosis I can lead to aneuploidy in eggs. The information discovered in this thesis work provides insight into the basic machinery that controls meiosis and more importantly will pave the way for the development of appropriate diagnostics and interventions to help women achieve pregnancy with egg cells containing the correct number of chromosomes.

ETD_8715

Ph.D.

Includes bibliographical references

by Alexandra Legeza Nguyen

doi:10.7282/T3RN3C96

ETD doctoral

The author owns the copyright to this work.