Research
Overview
Dr. Carl Thummel retired at the end of 2023 after 37 years of research in the Department of Human Genetics at the University of Utah and the Howard Hughes Medical Institute. During this time, studies in the Thummel lab focused on several related areas of research using the fruit fly, Drosophila melanogaster, as a model system:
1. Roles for the steroid hormone ecdysone in regulating metamorphosis during Drosophila development. At the end of larval development, and several hours later in prepupae, pulses of ecdysone define the end of the larval life stages and the onset of terminal differentiation into the adult form. Dynamic changes in ecdysone concentration are transduced into waves of transcription factors that coordinate the induction and repression of secondary-response target genes. It is the ecdysone-activation of these regulatory hierarchies that directs the animal through the complex behavioral and morphological changes associated with metamorphosis. This system provides an ideal opportunity to study differential gene regulation in response to a hormonal signal and the downstream effects on eukaryotic development. It also provides an ideal opportunity to understand the molecular mechanisms that coordinate systemic developmental transitions.
2. The Drosophila genome encodes 18 canonical nuclear receptors, with representatives of all the major vertebrate classes. The Thummel lab performed a systematic reverse genetic characterization of this gene family, focusing on nuclear receptors that have close mammalian homologs, in an effort to expand our understanding of their roles in development and maintaining metabolic homeostasis. This work included functional studies of the HNF4 and ERR nuclear receptors demonstrating that they control major metabolic transitions during development. HNF4 acts in the oenocytes of young adults to promote the biosynthesis of complex hydrocarbons that are required for waterproofing the adult cuticle. In contrast, ERR is required to coordinately induce the major genes in glycolysis in larvae and newly formed adults. This function supports the metabolic demands of larval growth and adult metabolism. In addition, the Thummel lab discovered that most genes acting in the major metabolic pathways of glycolysis, lipid metabolism, the TCA cycle, and electron transport chain, are coordinately regulated during development. The factors that mediate these global switches in metabolic gene expression, however, remain unknown.
3. Finally, through a fruitful collaboration with Jared Rutter's lab in the Department of Biochemistry, the Thummel lab studied the biological and metabolic functions of key evolutionarily conserved mitochondrial proteins (MCPs). In 2012, this work led to the discovery of the long-sought mitochondrial pyruvate transporter, which is responsible for transporting the end stage of glycolysis - pyruvate - into mitochondria for oxidative metabolism. This work provided a new foundation for understanding the roles of pyruvate metabolism in health and disease. Studies of other MCPs identified by the Rutter lab also provided insights into new aspects of mitochondrial function.
