Neurobiology

Charles J. Weitz, M.D., Ph.D.

Robert Henry Pfeiffer Professor of Neurobiology

Molecular Biology and Genetics of Biological Clocks

We study the molecular biology and genetics of circadian clocks, endogenous oscillators that drive daily rhythms in behavior and physiology. Under natural conditions, circadian clocks become precisely synchronized, or entrained, to the 24-hour light-dark cycle by the action of light on circadian photoreceptors. Together the intrinsic rhythms of the circadian clock and its entrainment to light-dark cycles control the temporal organization of complex behavioral and metabolic programs. In flies and mammals, the master circadian clock regulating behavioral activity is located within specific clock cells in the brain. Of late it has become clear that multiple peripheral tissues in mammals contain circadian clocks, but the roles of peripheral clocks and their relationship to the central clock are not yet understood.

A general picture of how circadian clocks are built has emerged in recent years from studies of the first handful of clock genes to be cloned. The core mechanism is a transcriptional feedback loop, wherein the products of several clock genes cooperate to inhibit the transcription factors responsible for their own activation. The molecular components of circadian clocks are conserved between flies and mammals, but in mammals there has been a multiplication of some of the clock genes, resulting in a negative feedback loop of greater complexity than that of Drosophila.

We use molecular biology, biochemistry, and genetics to investigate the mammalian circadian system. The focus of our efforts has been to identify and characterize molecular components of circadian clocks and to identify molecular pathways by which central circadian clocks drive rhythms in locomotor activity, feeding, and drinking. Recently we have begun to investigate the physiological roles of peripheral clocks.

Figure Legend: Heparin-Binding Epidermal Growth Factor (HB-EGF) in the suprachiasmatic nuclei. The image shows fluorescence from a coronal section of mouse brain immunolabelled for HB-EGF. Cells of the suprachiasmatic nuclei, site of the master circadian clock in mammals, are prominently labelled. Very few other sites in the adult brain show labelling. HB-EGF and a related factor, TGF-alpha, have been implicated as messengers in the daily cycle of behavioral activity controlled by the circadian clock.