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Carl S. Thummel

Professor of Human Genetics

B.A. Colgate University

Ph.D. University of California, Berkeley

Research

References

carl.thummel@genetics.utah.edu

Carl Thummel's Lab Page

Research

Small lipophilic hormones, including steroids, retinoids, and thyroid hormone, play a central role in the development and physiology of higher organisms. These signals are transduced by members of the nuclear receptor superfamily that act as hormone-dependent transcription factors, reprogramming gene expression within a target cell. Extensive studies in vertebrate systems have defined the molecular mechanisms by which nuclear receptors control promoter activity. In contrast, much less is known about the events that occur downstream from the receptor. It is difficult to identify hormone-regulated target genes in vertebrates and it remains unclear how these genes propagate the hormonal signal to direct appropriate biological responses in the animal.

We are using the fruit fly, Drosophila melanogaster, as a model system for studying the molecular mechanisms of hormone action and nuclear receptor function. The Drosophila genome encodes 18 nuclear receptors, compared to 48 in humans and 284 in C. elegans, providing the smallest complete set of receptors known in a genetic model system. We are taking a genomic approach toward characterizing Drosophila nuclear receptor regulation and function. To date, we have characterized the temporal expression patterns of all detectable nuclear receptors throughout the fly life cycle. We analyze the phenotypes associated with both loss-of-function and gain-of-function mutations as a means of determining gene function. Using heat-inducible expression of dsRNA for RNAi provides us with the temporal control that is needed to study the later functions of genes that are required for early development. By raising antibodies against the encoded proteins we can determine their spatial patterns of expression as well as their binding sites in the giant polytene chromosomes, identifying potential direct regulatory targets. We use microarrays to determine the effects of loss-of-function and gain-of-function mutations on gene expression, and classify these targets into functional groups by bioinformatics. Most recently, we have used metabolic profiling to determine effects of nuclear receptor mutations on specific metabolic pathways, linking these functions to key target genes identified in our microarray studies as well as developmental defects. Taken together, our goal is to use the fly as a model system for understanding how nuclear receptors regulate growth, metabolism, and development, with a focus on understanding the crosstalk between critical metabolic checkpoints and developmental transitions.

Much of the current work in our lab is focused on roles for nuclear receptors in metabolic homeostasis. Recent examination of DHR96 mutants revealed that they have reduced levels of triglycerides and are starvation sensitive, while DHR96 overexpression results in animals that are hyperglycemic, obese, and starvation resistant. Experiments are underway to examine the molecular basis for these defects in the DHR96 mutants. dHNF4 null mutants are hypoglycemic, obese, and sensitive to starvation. Microarray studies and other experiments indicate that these phenotypes are due to a central role for dHNF4 in sensing free fatty acids and regulating energy homeostasis through lipid β-oxidation. dERR null mutants have been created by gene targeting, and lead to lethality during early larval stages. Ongoing studies indicate central roles for this receptor in carbohydrate metabolism and mitochondrial function. Finally, experiments are underway to determine whether DHR3 contributes to lipid metabolism in a manner analogous to its vertebrate ortholog, RORα. The long-term goal of these studies is to exploit our ability to link Drosophila nuclear receptors with defined transcriptional cascades and specific biological responses as a means of furthering our understanding of how nuclear receptors control metabolic homeostasis and contribute to human disease.

References