Investigating autoimmunity in the etiology of premature ovarian insufficiency in a mouse model.

Premature ovarian insufficiency (POI) is a major cause of infertility, yet its underlying mechanisms remain poorly understood. The double-mutant (DM) mouse, featuring oocyte-specific deletion of mannosyl (α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (Mgat1) and core 1 β-1,3-galactosyltransferase (C1galt1), develops early-onset POI and offers a valuable system to investigate causes. This study explored whether autoimmunity leads to POI in DM mice. We transplanted control and DM neonatal ovaries into immunocompromised hosts. Three months post-transplantation, follicular development was assessed. While both DM and control ovarian grafts contained follicles, only control ovaries showed healthy progression through to the antral stage. In contrast, DM ovaries exhibited a marked developmental block at the primary stage. In DM follicles, oocytes were smaller, and granulosa cell (GC) number and area were reduced at all follicular stages present. There was a strong correlation between oocyte growth and GC proliferation in controls, but was weaker in DM, suggesting disrupted oocyte-somatic cell communication. Analyses showed strong anti-Müllerian hormone (AMH) in Control GCs, whilst DM levels were less than half of the control, indicating compromised GC function in DM ovaries. Forkhead box L2 (FOXL2) was also reduced in DM follicles compared to control GCs. The persistence of follicular defects, including reduced AMH and FOXL2 levels, in DM ovaries even in severe combined immunodeficient mice reveals that POI is not due to autoimmunity and the phenotype results from intrinsic defects in follicular development caused by the oocyte-specific mutation. These findings underscore the role of oocyte-GC interactions in follicle development and contribute to our understanding of POI pathogenesis.