Insights into the Molecular Mechanisms of Temperature Compensation from the Drosophila Period and Timeless Mutants

The relative constancy of the circadian period over a wide range of temperatures is a general property of circadian rhythms. Insights into the molecular mechanisms of temperature compensation are emerging from genetic and molecular genetic studies of the period (per) and timeless (tim) genes in Drosophila. These genes encode proteins that are thought to be part of a negative feedback cycle, which results in circadian oscillations of both per and tim mRNA, as well as a complex of the two proteins. Complex formation is temporally regulated and apparently necessary for nuclear localization of both per and tim proteins. While insights into the roles of per and tim in temperature compensation have been intriguing, they have also been somewhat perplexing. For instance, the interaction of wild-type per peptides is relatively insensitive to temperature in the yeast two-hybrid assay or in assays employing in-vitro-translated peptides, while the interaction of per^L mutant peptides is reduced at a high temperature. Apparently, the per^L mutation increases an intramolecular interaction between different parts of the per peptide in these assays, and this interaction reduces the amount of per homodimer. On the other hand, the same assays show that the intermolecular interaction between the per and tim peptides is reduced at a high temperature by the per^L mutation; this reduction does not require the competing intramolecular interaction. Despite this difference, in all of the experiments employing these assays the per^L mutation has rendered per-per and per-tim peptide interactions sensitive to high temperature, so it is likely that one or both of these reduced interactions contribute to the longer circadian periods at high temperature in per^L mutant flies. However, the tim^SL and per^S mutations, as well as deletion of the Thr-Gly repeats from per, affect temperature compensation but have not been shown to affect these molecular interactions of per and tim. Finally, a recent report of oscillating per and tim proteins in the cytoplasm (rather than the nuclei) of silk moth neurons may suggest an alternative mechanism for per and tim function in these cells. (Chronobiology International 14(5), 455–468, 1997)