PROJECT SUMMARY Normally, women undergo menopause in their early fifties due to exhaustion of the pool of oocytes called the “ovarian reserve”. Oocytes are generated in large numbers during embryonic development, but the vast majority undergo programmed cell death; the remaining oocytes become enclosed within quiescent primordial follicles that make up the ovarian reserve. Pathologic development of the ovarian reserve leads to infertility or early reproductive senescence. Furthermore, meiotic errors in oocytes cause germ cell death or result in developmental defects such as aneuploidy. The molecular signals within the embryonic ovary that determine the upper and lower limits for oocyte numbers are unknown. The long-term goal of our laboratory is to identify signaling pathways that control oogenesis and thus, female reproductive lifespan. The bone morphogenetic proteins (BMPs) are a large subgroup of the transforming growth factor beta family and have conserved roles in primordial germ cell specification and development. The BMPs are known morphogens whose activity must be strictly regulated during development or pathology and disease results. There are a number of secreted extracellular BMP-binding proteins that act as molecular sinks to negatively regulate the amount of BMP “sensed” by a signal-receiving cell. Two of these BMP antagonists, GREMLIN-1 and GREMLIN-2 have genetic variants associated with primary ovarian insufficiency (POI) in women. We tested the developmental role of Grem1 and Grem2 by generating single and double knockout mice for Grem1 and Grem2. These mice display a range of defects in embryonic ovary development including changes to oocyte number and altered meiosis. The aims of this proposal are designed to (1) determine how loss of Grem1 and/or Grem2 alters embryonic ovary development; and (2) determine which signaling pathways are dysregulated in embryonic ovaries of mutant mice that drive changes in germ cell numbers. Collectively, our studies stand to uncover fundamental mechanism that regulate embryonic ovary development and oocyte numbers, which are essential for mammalian female reproduction and reproductive lifespan.