Understanding how the Nuclear Receptor HR4 Influences Germline Stem Cell Lineages

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PROJECT SUMMARY Adult stem cells (SCs) are required to maintain tissue homeostasis and for repair in response to injury. Many external stimuli such as age, infection, and diet can influence SC behavior and function. Circulating factors including steroids, fatty acid derivatives, and metals act through nuclear receptors (NRs) to modulate the physiology of an organism in response to the environment. NRs are widely expressed transcription factors essential for development, metabolic processes, and reproduction. Mutations in NRs are associated with multiple cancer types and metabolic diseases. However, how the simultaneous actions of any given NR in multiple organs and cell types are integrated to regulate SC lineages remains unknown. Our lab and others have previously shown that NR activity in the Drosophila ovary itself regulates oogenesis. The ecdysone heterodimeric receptor composed of the Ecdysone Receptor and Ultraspiracle controls GSC maintenance and division, and differentiation of GSC progeny. In addition, Ecdysone-induced protein 78C is required for establishing the correct GSC number and for egg chamber viability; whereas, EcR and E75 are required for progression through vitellogenesis. The mechanisms whereby NR signaling in adult somatic tissues influence the GSC lineage, however, are largely unknown. I hypothesize that HR4 (an understudied NR) activity is required both in the germline and in one or more somatic tissues (through downstream secreted factors) to control key regulatory checkpoints during oogenesis. To test this hypothesis, I will (1) identify the tissues and cell types that require HR4 activity to influence oogenesis and (2) determine the downstream targets of HR4 in different tissue required to regulate oogenesis.