College of Science and Health Theses and Dissertations

Date of Award

Summer 8-22-2014

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Margaret Silliker, Ph.D.

Second Advisor

Jingjing Kipp, Ph.D.

Third Advisor

Eric Norstrom, Ph.D.

Abstract

The ovaries are the female reproductive organs that are located on either side of the uterus. They contain eggs and secrete hormones that are critical for female reproduction. Each follicle consists of an egg at the center, surrounded by multiple layers of somatic cells. These eggs undergo various stages of development wherein the follicular structure matures as a whole; the hormones and growth factors secreted by the somatic cells are essential for the maturation of the egg while the signaling molecules produced by the egg are crucial for somatic cell proliferation and follicle maturation and development.

Thus, mammalian ovarian follicle formation and development involves the establishment of the initial follicle pool, follicle growth, proper maturation of eggs, and timely production and release of hormones and the mature eggs. This process is essential for propagation of the species as well as for development and homeostasis of the female reproductive system[1]. Abnormalities in the regulation and development of ovarian follicles such as inadequate maturation of the follicle due to inadequate cell-cell interactions and signaling between the somatic cells and the egg can lead to infertility and ovarian diseases, for instance Premature Ovarian Failure (POF), Polycystic Ovary Syndrome (PCOS) and ovarian cancer.

These diseases lead to a loss of fertility due to the formation of immature or unhealthy follicles and/or oocyte development. Both intraovarian and extraovarian factors play a role in regulating the development of follicles. However, factors involved in follicular growth and survival are not well defined. Recently, studies have suggested that the potent morphogen retinoic acid (RA) plays a role in the development of a healthy ovary[1, 2]. However, the underlying mechanism is not understood. Germ cells in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to retinoic acid[2]. Nevertheless, the timing and regulation of meiosis vary amongst the sexes. It was determined that high levels of RA were necessary for initiation of meiosis in the ovary and the testes; however, while RA is required for germ cell development in the embryonic ovary, it is required during the juvenile and adult stages of testicular functioning[3, 4]. Cyp26b1, a member of the Cyp450 family of enzymes degrades retinoic acid in the ovary and the testes thereby limiting gonadal development [1, 3, 5]. However, information about the role of RA and Cyp26b1 in the gonads is limited. It is therefore necessary to further elucidate the roles of both RA and Cyp26b1 in ovarian and follicle development.

The purpose of this study is to examine the roles of Cyp26b1 and RA in mouse ovarian follicle development. This will be done by performing in vitro follicle culture and ovary culture with treatments including retinoic acid, the Cyp26 inhibitor R115866 and the RA metabolism inhibitor Liarozole and monitoring their effects on follicular and ovary growth. We expect the findings from this study to contribute significantly to infertility treatments and disease prevention, as being able to successfully grow follicles invitro could help the large population of women whose difficulty with conceiving is due to an immature and underdeveloped follicle pool.

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