Generation and Validation of a Conditional Circadian Reporter Mouse

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

Most aspects of physiology have 24-hour rhythmicity. The master clock regulating circadian physiology and behavior is located in the brain, in the suprachiasmatic nuclei (SCN). Other tissues also generate rhythms of gene expression and have near-24-hr rhythms in function. An enduring question in the field is how the rhythmicity in different cells and tissues is coordinated. There is a significant unmet need for lines of mice that allow monitoring of circadian rhythms in specific tissues and cell types. The objective of this proposal is to generate and validate two novel lines of mice expressing luciferase in a rhythmic manner. In one line of mice, luciferase expression will be conditional on Cre recombinase and in the other line, luciferase is expressed in a non-conditional way. These lines will be generated by modifications of the highly rhythmic and widely expressed gene encoding albumin D-element binding protein (DBP). Our proposed studies will characterize these reporter lines for utility in generating bioluminescence rhythms in a variety of tissues, including liver, pancreas and brain, will verify the Cre-dependence of luciferase activity in the Cre-dependent line, and will verify that the genetic targeting event does not alter behavioral or molecular rhythmicity of the animals bearing it, as necessary for this to be a useful circadian reporter. We anticipate these lines of mice will be valuable to many investigators studying circadian rhythms in brain and peripheral tissues, and will facilitate studies of the desynchrony among tissues that occurs following shifts of the light-dark cycle. Once validated, these lines of mice will be distributed to qualified investigators directly and via the Jackson Laboratories repository.