Marvin Wagner Professor and Chair
Medical College of Wisconsin
Department of Cell Biology, Neurobiology & Anatomy
8701 Watertown Plank Road
Milwaukee, WI 53226-3548
(414) 955-6517 (fax)
PhD, Southern Illinois University, 1973
Postdoctoral, Columbia University College of Physicians and Surgeons
Dean's Senior Leader Spotlight 2014 (PDF)
Program in Cell and Developmental Biology
Program in Neuroscience
Positions are currently available for PhD students and Postdoctoral Fellows.
Please contact Dr. Joseph Besharse at email@example.com or visit our Postdoctoral Positions web page.
Cellular and molecular basis of circadian rhythmicity in peripheral oscillators; molecular/cellular basis of trafficking of the transduction machinery in retinal photoreceptors
Circadian Clocks in the Eye and Liver: We are studying the cellular and molecular basis of circadian rhythmicity in the retina and other peripheral oscillators such as liver. Many features of photoreceptor and liver metabolism occur in a rhythmic pattern, and a central feature of this regulation is a "circadian clock" that provides endogenous timing signals independent of external cues. We have shown that retinal photoreceptors are the site of a circadian clock and others have shown that the liver hepatocytes are also clocks. Current work is derived from genetic models such as Drosophila in which rhythmically expressed "central clock genes" interact in coupled feedback loops to generate self-sustained circadian oscillations of clock gene expression. This central "clockwork", in turn, controls the rhythmic expression of downstream "clock-controlled" genes that are critical for circadian rhythms of cell function (see Figure 1).
The current major focus of the laboratory is to use mouse genetics to study the role of the central "clockwork" genes, Period and Clock in the retina and the role of the clock regulated genes Nocturnin and Usp2 downstream of the circadian clock. Because circadian organization is widespread in the retina and controls fundamental pathways such as turnover of the phototransduction machinery, it has long been assumed that disruption of circadian clock organization would have a major impact on retinal function. We are capitalizing on targeted mutations in mice of "central clockwork" genes to directly test this assumption. We have also developed targeted mutations of the "clock-regulated genes", Nocturnin (an mRNA deadenylase) and Usp2 (a ubiquitin specific protease). We are studying the role of period genes (Per1, Per2, and Per3), Clock, Nocturnin, and Usp2 in rhythmic retinal function and testing the hypothesis that disruption of these genes causes functional deficits that can impair vision and lead to retinal degeneration.
Trafficking of Phototransduction Components in Photoreceptors: Turnover of photosensitive membrane throughout the life of a photoreceptor depends on maintenance of a delicate balance between photosensitive membrane assembly and degradation. These events are controlled by circadian clocks (see above). Both protein and lipid components are synthesized in the cell body and transported vectorially to the region of the sensory cilium where phototransduction organelle is assembled. The cilium is important in the transport of macromolecules from sites of synthesis in the cell body to the region of membrane assembly and in the morphogenesis of flattened discs. Our current work is directed at a model called intraflagellar transport (IFT) in which microtubule based motors (dynein and kinesin) move protein complexes along microtubule tracks into and out of the cilium (see Figure 2). The IFT model is thought to apply to all motile and sensory cilium structures among the eukaryotes; IFT proteins are required for cilium assembly and are found widely in both motile and sensory cilia. Recent work in mice carrying mutations in genes encoding the kinesin II motor and the IFT complex protein, IFT88, demonstrate that this pathway is required for assembly of the phototransduction system in photoreceptors (see Figure 3). Research in this laboratory is directed at organization of the IFT protein complex and its physical interaction with both cell specific cargo and with microtubule based motor proteins.
Figure 1. Diagram illustrating the relationship of the central clockwork (left) and clock regulated genes (right). Only the Per/Cry loop of the clock is illustrated. Clock regulated genes are downstream of the clock and involved in circadian function within cells.
Figure 2. The components of intraflagellar transport as revealed in the green alga, Chlamydomonas.
Figure 3. A model for intraflagellar transport in photoreceptors based on work of Pazour, et al., 2002.