Measuring the Functional Requirement of Ecdysone Receptor Transcriptional Regulation during Drosophila Development - To become a healthy adult, the generation of different tissues and organs must be synchronized along a common chronological timeline. One way this challenge is achieved is through systemic pulses of steroid hormones which provide organism-wide signals to coordinate and initiate key developmental events. Steroid hormones bind nuclear hormone receptors (NHRs), a conserved class of transcription factors that activate or repress target transcription depending upon the combination of bound coactivators and corepressors. This flexibility makes NHRs susceptible to nuanced changes in the cellular environment and uniquely powerful as a way to control important cell fate decisions. Because of this power, NHRs are notoriously difficult to study and our understanding of the molecular details underlying NHR regulation of cell fate decisions is shockingly incomplete. The major Drosophila NHR, Ecdysone Receptor (EcR), orchestrates developmental progression through the control of developmental signaling pathways. But how EcR exerts this control is unknown. To address this challenge, we created an innovative set of tools in Drosophila that disrupt key EcR:coregulator interactions, allowing us to assess the functional consequence of EcR on cellular decision-making. The ultimate goal of our work is to use our tools to tease apart the details of EcR transcriptional activity during Drosophila development. Our team of undergraduate researchers and Master’s students will simultaneously pursue two related specific aims: (Aim 1) that EcR activation is an important mode of transcriptional regulation for EcR signaling during development; and (Aim 2) that EcR transcriptional regulation directly regulates the growth and patterning of epithelial cells. These aims will be achieved through the use of sophisticated genetic tools and the use of transcriptional and cell signaling reporters to determine the cellular response to EcR transcriptional regulation. The proposed research is innovative because it leverages our research system to precisely disrupt EcR activity and measure the outcome and is significant because this project will provide an integrated view of EcR-repression and -activation on cellular decisions. Because the mechanisms of NHRs are conserved across metazoans, these data could provide insight into human NHR regulation of development and diseases. Critically, in keeping with the goals of the SuRE-FIRST award mechanism, this project will support the research excellence of the PI by providing protected time to recruit, train, and mentor talented undergraduates at a large, regional public university. The PI’s early career will be supported by an Advisory Committee of expert mentors who will provide critical career guidance as the PI establishes her supportive research program. Members of the Wardwell-Ozgo laboratory will gain hands-on experiences using an approachable model system and a wide variety of molecular, genetic, and biochemical techniques, and will be actively involved in project conception and execution, and the dissemination of results and findings through conference presentations and authorships on peer-reviewed manuscripts.
