Hormonal control of stem cells in the Drosophila ovary

About This Grant

PROJECT SUMMARY/ABSTRACT Stem cells endow tissues the ability to replace cells and maintain cellular diversity during remodeling or damage. Stem cells depend on both hormones and local signaling to regulate their activity in response to physiological demand. The molecular mechanisms by which this spatiotemporal regulation is achieved, however, are incompletely defined. To address this knowledge gap, our research program uses a well- described stem cell-based tissue, the Drosophila melanogaster ovary, to elucidate the molecular mechanisms underlying stem cell homeostasis. Ovarian germline stem cell (GSC) activity is governed by intrinsic cell cycle regulators and local bone morphogenetic protein ligands from adjacent somatic cells. Yet we and others demonstrated that GSCs are also responsive to the steroid hormone ecdysone, which is synthesized by differentiated ovarian cells and essential for ovarian function. Previous studies were unable to disentangle the pleiotropic effects of ecdysone, precluding identification of relevant molecular mechanisms in GSCs. Moreover, while ecdysone is the sole ligand for the Ecdysone Receptor (EcR), other nuclear receptors are also ecdysone- responsive, likely as transcriptional targets of EcR. The goal of our research program is to elucidate how GSCs integrate the ecdysone response with intrinsic cell cycle regulators and local signals from neighboring soma to successfully maintain stem cell homeostasis. In this proposal, we use novel genetic reagents for the manipulation of EcR specifically in GSCs with a combination of quantitative high resolution fixed imaging, live imaging, and single cell transcriptomics to identify the cell-autonomous mechanisms by which EcR controls asymmetric division. We focus on how EcR transcriptional targets 1) directly promote intrinsic cell cycle progression and the distribution of asymmetric determinants during mitosis, and 2) modulate the responsiveness of GSCs to other extrinsic signals. Overall, the proposed projects will provide fundamental insight into how a single steroid hormone can endow stem cells with the capacity to incorporate and respond to diverse signaling inputs, providing a sensitive response system that ensures stem cell longevity and continued production of differentiated progeny. Further, this work will inform future studies focused on elaborating the gene regulatory network that controls stem cell asymmetric division.