Keenan Bates

ORCID

http://orcid.org/0000-0002-4600-2920

Date of Award

Spring 5-15-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Circadian rhythms in gene expression and hormones are ubiquitous across species and across cell types. Circadian rhythms depend on a transcription-translation negative feedback loop that drives many daily rhythms in behavior and physiological processes. Circadian rhythms regulate many aspects of reproduction, such as fetal development and birth timing. Mammalian pregnancy presents a unique situation with circadian rhythms in the mom and, eventually, in the fetus. Prior studies showed that circadian rhythms develop in utero and that maternal signals, such as glucocorticoids, may act to entrain or drive daily rhythms in the fetus. However, there remains considerable debate about when and where these daily molecular oscillations first arise in development and which signals may be involved. We hypothesized that fetal circadian rhythms arise during pregnancy and synchronize to the mother prior to birth via maternal-to-fetal circadian communication. We monitored fetal clock gene expression in utero and found that fetal daily rhythms arise by E9. Our results indicate rhythms develop much earlier in the fetus than previously thought. We also found fetal rhythms synchronize to the mother by E16. Furthermore, mistimed daily glucocorticoids disrupt this synchrony. Additionally, we showed that the placenta exhibits intrinsic circadian rhythms beginning as early as E9 and blocking glucocorticoid signaling disrupted synchrony within the placenta. We conclude that fetal and placental circadian rhythms arise early in pregnancy and glucocorticoids may act as important entraining signals for these tissues. We also wanted to better understand the role of circadian rhythms in birth timing. Previous research indicated that circadian rhythms ensured birth occurred at a specific time of day, depending on the species. We hypothesized that mutations in clock genes would alter birth timing and gestation length. To test this, we examined gestation length, birth timing, and fetal development from multiple circadian mutant mouse lines. We found that Period1 performs a necessary role in the circadian gating of birth as loss of Period1 caused mice to give birth at random times of day. On the contrary, Period2 modifies the time of day of birth as mutations in this gene led to a ~6-hour shift in the timing of birth. Secondarily, our results demonstrate the importance of the Period2 gene in regulating gestation length. We conclude that the Period genes act as important regulators of labor. Taken together, these results highlight the complex role circadian rhythms have in regulating reproduction and development.

Language

English (en)

Chair and Committee

Erik Herzog

Committee Members

Sarah England, Laura Schulz, Paul Taghert, Thorold Theunissen,

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