Paul Hardin, PhD

Chair and Professor
Department of Biology
Director, Center for Research on Biological Clocks
Texas A&M University
College Station, Texas

A Brief History of Clocks Outside the Brain

Dr. Hardin was a postdoctoral fellow at Brandeis University from 1987–1991. He worked closely with Michael Rosbash and Jeff Hall on the topic of circadian rhythms (day/night sleep cycle) in the fruit fly.

Understanding how genes control behavior is a daunting challenge that attracted Dr. Hardin to Michael Rosbash’s lab within the Brandeis Neurogenetics group in 1987. At this time the period (PER) gene had been cloned, and intriguing information showing that PER protein immunoreactivity cycled in a circadian manner prompted Dr. Hardin to explore whether this cycling was due to an underlying cycle of PER mRNA. His resulting work showed that not only did per mRNA cycle, but also that PER protein feeds back to control cycling of its own mRNA.

Subsequent analysis from many labs not only support the circadian feedback loop model but add to its mechanistic detail and demonstrate that conserved feedback loops also control circadian timing in mammals. Widespread expression of PER in flies suggests that feedback loops operate in many tissues. Dr. Hardin’s lab went on to show that circadian feedback loops do indeed operate in the body tissues, and further analysis in the Hall and Kay labs using PER-driven luciferase reporter genes established that individual peripheral tissues contain autonomous light entrainable oscillators. However, the function of peripheral oscillators remained a mystery. Together with Stuart Dryer, the Hardin lab has shown that circadian oscillators in olfactory sensory neurons (OSNs) in the antenna were necessary and sufficient to control rhythms in the amplitude of physiological responses to odors. Recent work demonstrates that G-protein coupled receptor kinase 2 (Gprk2) is rhythmically expressed, and that levels of GPRK2 protein determine the amplitude of odor-dependent responses by regulating the dendritic localization of heteromeric odorant receptor complexes within OSNs. The circadian clock in OSNs also controls the amplitude of spontaneous activity spikes, which implies that the clock controls basic aspects of OSN membrane physiology. By identifying the targets of GPRK2 and characterizing the mechanism underlying OR dendritic localization rhythms they hope to define the clock output pathway that controls rhythms in olfactory physiology.