- B.S., Biology, Southern Methodist University, 1982
- Ph.D., Genetics, Indiana University, 1987P
- Postdoc., Brandeis University
Molecular Genetics of Biological Clocks
Work in my laboratory focuses on understanding the molecular circuitry that underlies circadian clock function in the fruit fly, Drosophila melanogaster . Like other organisms, these flies display daily rhythms in molecular, physiological and behavioral events that are controlled by an innate, genetically encoded, circadian clock. Much of our work revolves around the period ( per ) , timeless ( tim ), cycle ( cyc ), Clock ( Clk ), PAR domain protein 1 epsilon ( Pdp1 e ) and vrille ( vri ) genes, which form the core of the circadian time keeping mechanism, or oscillator, in Drosophila .
We previously found that the core mechanism underlying oscillator function in flies revolves around two interlocked feedback loops in gene expression. Subsequent studies showed that interlocked feedback loops are a conserved feature of the clock mechanism. The operation of these feedback loops is dependent on the heterodimeric bHLH-PAS transcription factors CLK and CYC, which bind E-box elements to activate the transcriptional feedback regulators vri , Pdp1 e , per and tim . VRI and PDP1 e proteins feedback to control the inhibition and subsequent activation of Clk transcription, respectively, while PER and TIM proteins feedback as a heterotrimeric complex with DBT kinase to inhibit CLK-CYC dependent transcription. These transcriptional regulatory events, along with post-translational control of protein accumulation, subcellular localization and degradation, maintain circadian cycles in gene expression that control rhythmic outputs. We are currently investigating transcriptional and post-transcriptional mechanisms that control when core feedback loop proteins function, with the ultimate goal of defining the molecular interactions that regulate the timing of events which make these feedback loops a circadian oscillator. In addition, we are identifying developmental factors that determine which cells will have circadian clocks.
This feedback loop mechanism operates autonomously in many neuronal and non-neuronal tissues throughout the fly. However, little is known about the rhythms controlled by different cell-specific oscillators with the exception of locomotor activity, which is controlled by "lateral neurons" within the central brain. In collaboration with Dr. Stuart Dryer at the University of Houston, we discovered that olfactory responses are rhythmic. These rhythms, as measured by electroantennagrams (EAGs), continue in constant darkness, are dependent on per and tim, and are controlled by oscillators in peripheral tissues. We recently showed that circadian oscillators in antennal neurons are both necessary and sufficient to mediate olfaction rhythms, indicating that these cells act as independent circadian pacemakers. Our studies are now focused on determining what component of the olfactory system is controlled by the clock and what effect these rhythms have on behavior.
Current Genetics Students:Courtney Caster
- Molecular, Cellular and Developmental Genetics:
Molecular genetics of biological clocks in Drosophila