Unveiling the Role of Shp2 in Follicular Development and Fertility Through Targeted Ptpn11 Deletion in Mouse Granulosa Cells

Follicle development relies heavily on granulosa cells for growth factors and cytokine-induced signals mediated by various receptors. Previously, we found that Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is critical for follicle-stimulating hormone receptor (FSHR) signal transduction in bovine granulosa cells near premature oocytes. To further investigate the role of SHP2 in ovarian follicular development, we generated granulosa cell-specific SHP2 knockout mice and cultured SHP2 knockout granulosa cells and female gonads. Deletion of SHP2 in primary granulosa cells diminished ERK phosphorylation and CREB nuclear localization, notwithstanding FSH and LH treatment. In vitro culture of SHP2-deficient gonads (E12.5) resulted in arrested follicular growth at the primary stage. Female SHP2fl/fl; Cyp19a1-Cre mice exhibited subfertility with small ovaries, reduced ovulation, and absent corpus lutea compared to controls. RNA-Seq analysis revealed a significant downregulation of genes associated with the steroidogenic pathway (e.g Cyp19a1, Hsd17b2, and StAR). Furthermore, SHP2 deletion significantly reduced the expression of ovulation-related genes such as Ptgfr, Ptgs2, Edn2, Ptx3, and Lipg.
Additionally, the expression of important markers for granulosa cell proliferation, such as Procr, Fhl2, and Wnt2, was significantly reduced. These findings indicate that SHP2 regulates folliculogenesis via the activation of the ERK1/2/CEBPα/β signaling pathway. Given its critical role in steroidogenesis and ovulation, SHP2 represents a potential therapeutic target for ovarian dysfunction and infertility.