Endocrine Abstracts

The oocyte-derived growth and differentiation paracrine factor BMP15 has emerged as an essential regulator of the ovarian folliculogenesis, from evidences in animal models (knockout mice and sheeps with naturally occurring mutations) and humans. Indeed, several BMP15 mutations have been identified in association with primary ovarian insufficiency (POI), a heterogeneous and frequent fertility disorder characterized by the premature depletion of ovarian follicles in women <40 years. Despite the frequent inheritability of POI, genetic alterations still explain only few cases and we hypothesized that the elucidation of the BMP15-dependent effects on granulosa cells (GCs) would give interesting insights for advancements in this direction. Through a global approach for large-scale gene-expression profiling, the analysis of the transcriptome induced by recombinant human BMP15 action on primary cultures of human Granulosa Cells (GCs) was performed. The GCs were obtained from fertile women undergoing IVF and then stimulated in triplicates with BMP15. Treated and untreated GCs were harvested after 0, 2 and 6 h, to evaluate early and late regulated genes. RNAs from each condition were processed for hybridization on Illumina beadchips. Statistical analysis identified about 100 differentially expressed genes (FDR q-value <0.001) already 2 h after treatment (cutoff fold-change >2). As expected, we found that BMP15 induces genes important for the modulation of the BMP/TGFbeta signaling. Interestingly, BMP15 inhibits the GCs expression of genes important for ovarian physiology (follistatin, TGFB3R, steroidogenesis enzymes and metalloproteases family members) and regulates apoptotic and proliferative genes (BCL and MAPK families), thus indicating BMP15 as a master regulator of folliculogenesis processes. In conclusion, this is the first comprehensive panel of transcriptomic effects induced by BMP15 on human GCs. The analysis of such regulated genes should allow the selection of novel candidates to be screened in POI cohorts for the comprehension of the pathogenic mechanisms underlying POI.