Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biology

First Advisor

Michael A. Lampson

Abstract

The goal of the first meiotic division is the faithful segregation of homologous chromosomes to produce a gamete with proper ploidy. To achieve this, chromosomes must align at the metaphase plate of a bipolar meiotic spindle, biorient and separate equally at anaphase. Compared to mitosis, meiotic divisions are associated with extra challenges for the mitotic cell division machinery. First, meiotic spindles are acentrosomal, and bipolarity establishment is more complex than during mitosis. Second, homologous chromosomes must biorient and separate during meiosis I, unlike during most other cell divisions, which separate sister chromatids. Meiotic cells have adapted the mitotic enzymatic machinery to regulate these meiotic processes. This dissertation describes the uniquely meiotic properties of two mitotic master regulators, Aurora B kinase (AURKB) and Cyclin-dependent kinase 1 (CDK1). Chapter 2 addresses why mammalian oocytes have a germ-cell specific homolog of Aurora B kinase, Aurora C (AURKC). AURKB is required for chromosome biorientation and segregation during mitosis and meiosis, and most experimental evidence suggests that AURKC is not functionally different. To investigate the role of AURKC, the current study takes advantage of AURKC knock-out mouse oocytes and preimplantation embryos. Chapter 2 shows that the effect of lacking AURKC becomes more pronounced and deleterious as meiosis and early embryonic divisions progress. I conclude that AURKC is likely required to compensate for the loss of AURKB protein, which is rapidly degraded during meiosis. Chapter 3 investigates CDK1 as the molecular clock responsible for the timing of kinetochore-microtubule attachments during meiosis I. Likely because of the prolonged spindle formation and bipolarity establishment in the acentrosomal mouse oocyte meiosis, kinetochore-microtubule attachments are delayed until late in metaphase I. This is unlike mitosis, where attachments are constantly made and broken. Chapter 3 answers the long-standing question of how attachments are timed. Using CDK1 inhibition and precocious activation techniques, I find that this kinase controls the timing of kinetochore-microtubule binding. The studies reported in this dissertation demonstrate the unique adaptations found in mitotic kinase AURKB and CDK1 functions to the unique requirements of meiotic divisions.

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