Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Amita Sehgal

Second Advisor

Thomas A. Jongens

Abstract

Although there has been much progress in deciphering the molecular basis of the circadian clock, major questions remain about clock mechanisms and about the control of behavior and physiology by the clock. In particular, mechanisms that transmit time-of-day signals from the clock and produce rhythmic behaviors are poorly understood. Also, it is not known why rest:activity rhythms break down with age. In this thesis, we used a Drosophila model to address some of these questions. We identified a pathway that is required downstream of the clock for rhythmic rest:activity and also explored the mechanisms that account for deterioration of behavioral rhythms with age. By investigating candidate circadian mutants identified in a previous genetic screen in the laboratory, we discovered a circadian function of a microRNA gene, miR-279. We found that miR-279 acts through the JAK/STAT pathway to drive rest:activity rhythms. These effects occur downstream of the clock and thus define a novel output circuit. In our work on aging, we found that although old flies have a longer period and an unstable phase, central clock function is robust. Thus, the deterioration also occurs downstream of the clock, in either the circadian output pathway or in the sleep homeostatic system. Indeed, a genetic manipulation that improves rhythms in old flies has been implicated independently in circadian rhythms and sleep. In addition, some environmental manipulations can strengthen sleep:wake cycles in old flies. In short, the studies described in this thesis contribute to our understanding of the molecular underpinnings of circadian output and suggest that such outputs are affected by aging. In the long term, these studies may contribute to finding treatments for clock dysregulation or age-related circadian disorders.

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