Adult stem cells have remarkable ability to self-renew and generate differentiated cells that maintain homeostasis in adult tissues. They have been shown to be located in and regulated by the niche. A major challenge in stem cell research is to identify and understand functions of extrinsic signals and intrinsic factors that control stem cell self-renewal. The long-term goal of this project will be to gain a greater understanding of how stem cell self-renewal is controlled by intrinsic factors and niche signals using Drosophila ovarian germline stem cells (GSCs) as a model system. The Drosophila ovary represents an attractive system to study stem cells and their niche at the molecular and cellular level due to powerful genetics and easily identified stem cells. We have recently shown that Gbb/BMP5-8 and Dpp/BMP2-4 from the niche control GSC self- renewal by repressing expression of a differentiation-promoting gene bam. We have also shown that E- cadherin-mediated cell adhesion is required for anchoring GSCs to their niche and that a chromatin remodeling factor ISWI and a translation regulator Pelota are required for controlling GSC self-renewal. However, it still remains largely unclear how niche signals cooperate with intrinsic factors to control GSC self-renewal. Three specific aims of this proposed study are:(1) to use a combination of molecular, genetic, biochemical and cell biological approaches to determine how BMP signaling interacts with chromatin remodeling factors to repress bam expression and thereby maintain self-renewal; (2) to use a combination of molecular, genetic and cell biological approaches to investigate how niche activity is regulated by studying genetic relationships between a newly identified niche gene shk and the BMP pathway; (3) to molecularly and genetically characterize genes that are required for GSC self-renewal. The results from this proposed study will lead to a greater understanding of how niche signals and intrinsic factors work cooperatively to control GSC self-renewal. The mechanisms controlling Drosophila ovarian GSCs are likely fundamental to understanding adult mammalian stem cells since stem cells from diverse organisms share similar "sternness" properties. Stem cells have been advocated to treat a variety of degenerative diseases such as Parkinson's and Alzheimer's diseases, and have also been connected to cancer and aging. Therefore, this proposed study will surely contribute to a better understanding of stem cell biology, cancer formation and aging as well as to using stem cells in future regenerative medicine.