51 Targeted PTPN11 deletion in mice granulosa cells revealed the importance of SHP2 for female fertility

Ovarian follicle development and oocyte meiotic maturation rely heavily on the surrounding somatic cells. Several proteins signaling pathways are essential during pre-granulosa cell differentiation, proliferation, and primordial follicle stimulation. Src-homology protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed and interacts with a variety of receptors and adaptor proteins to promote signaling, which is crucial for tissue functioning. In this study, we investigated the function of SHP2 in ovarian follicle formation by generating granulosa cell-specific SHP2 knockout mice. The crossing of Cyp19a1-Cre and SHP2^flox/flox mice and resultant congenic mice were infertile, with a significantly small ovary size and a very low number of primordial follicles (384 ± 19.34 vs. 137 ± 3.28). Previously, we found that SHP2 shows nuclear localization in the premature oocyte surrounding granulosa cells, and FSH treatment transports SHP2 to the cytoplasm for transduction of FSHR signals. Here we found that SHP2KO significantly altered the granulosa cells steroidogenesis, a downstream mechanism of the FSH pathway. Our RNA-Seq data showed a significant reduction in steroidogenic pathway genes such as Hsd17b2 (fold change [FC] −2.842183), Hsd3b6 (FC −3.551589), Cyp17a1 (FC −10.35926), Cyp19a1 (FC −4.443796), and StAR (FC −2.842183) genes. Moreover, SHP2 deletion from in vitro cultured gonads obtained from E12.5-day female fetuses largely reduced the follicular number, further confirming the importance of SHP2. Mechanistically, SHP2 is required for granulosa cell proliferation during the primary to the preovulatory stage of follicular growth via FSH signaling pathway. We concluded that SHP2 expression is essential for female fertility, ovarian follicle development, and oocyte maturation.