A Large Network of Interconnected Signaling Pathways in Human Ovarian Follicles is Supported by the Gene Expression Activity of the Granulosa Cells

Human follicular fluid (hFF), as an extra oocyte microenvironment, is essential to the biological processes of oocyte development. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 426 proteins as consistently present in hFF from different participants. According to our gene chip data, the granulosa cells in the follicle locally produce 235 of these proteins. These data suggest that the granulosa cells actively participate in the follicular development by synthesizing important molecules to support the activity of pathways that are essential to oocyte development and genomic preservation. The computational Ingenuity Pathway Analysis (IPA) suggests that the identified proteins have well-established functions in the pathways of steroidogenesis, cell-to-cell signaling and interaction, molecular transport, the antioxidative system, interleukin 1 (IL-1) and IL-6 signaling, liver X receptor/retinoid X receptor (LXR/RXR) activation, and the interconnective insulin-like growth factor and lipid metabolism networks. The hFF peptide composition is likely to serve not only the inflammatory follicular state as has been previously suggested; rather, it is a highly diverse and multifunctional environment with several interconnected pathways. These results provide us with important knowledge related to the environment in which the oocyte develops as well as the molecular basis for controlling the process independently of blood supply.