SAT-LB037 Gremlin-2 Regulates Ovarian Function in Mice

1-2% of women are affected by premature ovarian failure also termed premature ovarian insufficiency (POI). While much of POI is driven by loss of oocytes within the ovarian reserve, the underlying mechanism(s) or pathophysiology is unclear. Bone morphogenetic proteins (BMPs) play an essential role in primordial germ cell (PGC) specification and ovarian folliculogenesis. BMP signaling is regulated by extracellular binding antagonists, which include Gremlin-1 and Gremlin-2. We previously showed that deletion of Grem1 in mice causes a reduction in germ cell numbers by birth, altered meiotic progression, and changes in initial formation of the ovarian reserve. GREM1 shares 65% amino acid identity with GREM2, although the role of GREM2 in ovarian folliculogenesis is not well understood. Using CRISPR-Cas9 engineering, we developed a novel knockout of Grem2 in mice. In contrast to Grem1(-/-), which has a perinatal lethal phenotype, Grem2(-/-) mice are viable. While Grem2(-/-) females had normal litter sizes, they had significantly fewer litters per month compared to control mice. By six months of age, Grem2(-/-) female mice displayed irregular estrous cycles, lower levels of serum anti-Mullerian hormone (AMH), and altered ovarian histology, including pathological infiltration of macrophages into the ovarian stroma. Grem2 is not detected in the wild type pituitary, and we did not detect changes in the serum gonadotropins in Grem2(-/-) mice, suggesting that the dysfunction of estrous cyclicity in Grem2(-/-) female mice is driven primarily by intraovarian changes that negatively affect the HPG axis. However, we have detected Grem2 in the wild type hypothalamus, though its functional significance in the brain is unclear. In the wild type ovary, Grem2 is expressed from ovarian somatic cells, and a candidate gene analysis indicates that there are significant changes in ovarian expression of kit ligand and Amh, two granulosa cell expressed genes with known roles in ovarian folliculogenesis. In total, our data indicate that GREM2 is necessary for normal ovarian physiology and may play a key role in HPG axis regulation. These studies were supported by NIH R01 HD085994 (to SAP), P30 CA125123 (Dan L. Duncan Cancer Center, BCM) and P50 HD28934 to (Ligand Assay Analysis Core, University of Virginia) Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.