Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Louis Muglia

Abstract

Successful reproduction is essential for survival of species. For humans, reproductive problems can cause large emotional and medical burdens. Evidence in both humans and rodents indicates that circadian rhythmicity is important for supporting reproductive function. A molecular clock orchestrates circadian rhythmicity. Impairment in fertility and parturition are observed in female mice expressing a mutant form of Clock, suggesting critical roles for clock genes in reproduction. Since the clock gene Bmal1, but not Clock, is necessary for the generation of circadian rhythmicity, exploring the role of Bmal1 in reproduction may yield a better understanding of the importance of the molecular clock in this process. We characterized the reproductive phenotype of Bmal1-/- females. These females were infertile, and our data suggests that implantation failure due to impaired steroidogenesis is a major contributor to this infertility. Expression of Bmal1 and other clock genes has been demonstrated in such tissues important for the early stages of the reproductive process as the ovary, oviduct, GnRH neurons, and non-gravid uterus. However, the expression of clock genes in tissues involved in the later stages of gestation has been largely unexplored. We determined that Bmal1 and other core clock genes are expressed in the gravid uterus, placenta, and fetal membranes of wild-type mice during the last third of gestation. Many of these genes were expressed in a rhythmic fashion throughout the circadian day suggesting the presence of operating peripheral molecular clocks in these tissues. The study of the role of Bmal1 in the late stages of the reproductive process is complicated by the infertility experienced by Bmal1-/- mice. To circumvent the problem of infertility and to examine the role of peripheral tissue Bmal1 expression in late gestation, we generated conditional Bmal1 knockout mice. These mice were used in concert with Telokin-Cre mice to disrupt Bmal1 specifically in the myometrium, the muscle portion of the uterus. Myometrial Bmal1 disruption was found to result in a disregulation of labor timing and altered expression of contractile-associated proteins. Results presented here demonstrate an importance of the core clock gene Bmal1 in both early and late stages of the reproductive process. These studies may lead to a better understanding of the roles of clock genes in supporting normal reproductive function in women.

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Permanent URL: http://dx.doi.org/10.7936/K7HT2MBV

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