Tubulin Polymerization Promoting Protein Affects the Circadian Timing System in C57Bl/6 Mice.

Rebecca Darrah,Thomas J. Kelley,Eric Barbato

doi:10.5334/jcr.207

Abstract

The circadian timing system (CTS) is a complex set of cyclic cellular mechanisms which serve to synchronize discrete cell groups across multiple organ systems to adapt the bodys physiology to a (roughly) 24-hour clock. Many genes and hormones have been shown to be strongly associated with the CTS, some of which include the genes Bmal1, Period1, Period2, Cryptochrome1, and Cryptochrome2, and the hormone melatonin. Previous data suggest that microtubule dynamics play an important role in melatonin function as it relates to the CTS in vitro, though this relationship has never been explored in vivo. The purpose of this study was to determine whether disruption of microtubule regulation in C57Bl/6 mice results in measurable changes to the CTS. To study the potential effects of microtubule dynamics on the CTS in vivo, we utilized a mouse model of microtubule instability, knocked out for the tubulin polymerization promoting protein gene (Tppp -/-), comparing them to their wild type (WT) littermates in three categories: locomotor activity (in light/dark and dark/dark photoperiods), serial clock gene expression, and serial serum melatonin concentration. These comparisons showed differences in all three categories, including significant differences in locomotor characteristics under dark/dark conditions. Our findings support and extend previous reports that microtubule dynamics are a modulator of circadian rhythm regulation likely through a mechanism involving melatonin induced phase shifting.

Highlights

The circadian timing system (CTS) is a complex set of cyclic cellular mechanisms which serve to synchronize discrete cell groups across multiple organ systems to adapt the body’s physiology to a 24-hour clock
LOCOMOTOR ACTIVITY wild type (WT) and Tppp -/- mice showed numerous differences in locomotor activity characteristics throughout the 12:12 LD photoperiod including onset time of activity rhythms in both the circadian and ultradian ranges as measured by Fast Fourier Transform (FFT) and mean counts per hour throughout the LD photoperiod
High amplitude signal in the circadian range and low amplitude signal in the ultradian range were detected with no significant differences between the WT and Tppp -/- groups

Summary

Introduction

The circadian timing system (CTS) is a complex set of cyclic cellular mechanisms which serve to synchronize discrete cell groups across multiple organ systems to adapt the body’s physiology to a (roughly) 24-hour clock. The cell groups responsible for regulation of the CTS function as oscillators, in which multiple circadian “clock” genes are expressed at varying levels rhythmically throughout the day. Dysfunction of the system, caused by endogenous or exogenous factors, has been linked to many disease processes, including disordered sleep, anxiety and depression, cardiac disease, immune dysfunction, and many others [4, 5]. Many genes and their protein products have been associated with the CTS, some of which include Clock, Bmal, Period, Period, Cryptochrome, and Cryptochrome2 [5, 6]. There are many endogenous factors known to entrain the CTS to some degree, including expression of certain genes and proteins, as well as melatonin production

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