Regulation of tissue stem cell lineages by nuclear receptor signaling

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PROJECT SUMMARY Stem cells are required for tissue maintenance and repair during the lifetime of an organism. Altered organism physiology can influence tissue homeostasis through disruption of endocrine tissues, resulting in changes in fat cell metabolism, steroid and hormone levels, and secretion of circulating factors within the body. Secreted factors communicate the physiological status of distant organs to one another. Nuclear receptors (NRs) are broadly expressed transcription factors with ligand-binding domains that mediate the effects of circulating factors throughout an organism. NRs are major regulators of energy homeostasis, including carbohydrate metabolism, fatty acid synthesis, and beta oxidation and play important roles in stem cell differentiation, metabolism, and tissue homeostasis. However, the mechanisms used by NRs to modulate the transcriptional landscapes in multiple organs and cell types to control distal stem cell lineages for proper tissue function are understudied. The Drosophila melanogaster ovary is an ideal model to understand how inter-organ communication mediated by NR signaling influences germline stem cell (GSC) lineages. Previous studies have shown that NRs act directly in GSCs to regulate oogenesis; however, there is emerging evidence that the activity of NRs in peripheral tissues indirectly influence the GSC lineage. For example, the NR Seven-Up (Svp) acts within adipocytes to influence GSC maintenance and early germline cyst survival and in hepatocyte-like cells to regulate survival of vitellogenic egg chambers. In addition, Hr4 is required in adult muscle to maintain GSCs and promote follicle growth. The goal of our research program is to determine how signaling downstream of transcription factors in different tissues influences circulating factors that regulate stem cell lineages and tissue function. In this proposal, we will use a combination of genetics, cell biology, and next- generation sequencing to address two major questions using NRs and the Drosophila ovary as models: 1) How do transcription factors coordinate their activity in multiple tissues and cell types to regulate stem cell behavior? 2) How is NR directed energy homeostasis maintained in organs to ensure survival of stem cell lineages and maintain tissue function? Overall, these projects will provide the foundation towards understanding the downstream mechanisms used by transcription factors in peripheral tissues to influence the behavior of adult stem cell lineages. Furthermore, this work will inform future studies focused on understanding how disrupted endocrine signaling results in tissue and organ failure.