Figure 3.

Schematic representation of PI3K/PTEN/AKT signaling pathways identified, mainly in the mouse, in the two components of the primordial follicle, pregranulosa cells, and oocyte, and of their major targets involved in maintaining the dormancy of the follicle including cell cycle in pregranulosa cells and survival, growth, and DNA integrity in the oocyte. As extensively discussed in the test, pregranulosa cells are arrested in the reversible GO cell cycle stage while the oocyte within the primordial follicle is maintained in a quiescent status, requiring the prevalence of survival upon proapoptotic factors, preservation of DNA integrity, and the inhibition of transcription necessary to its growth. In oocytes, all or a relevant part of these activities require the basal level of PI3K/AKT activity finely regulated by the KL/KIT system and PTEN. Activation or inhibition of AKT on its substrates are represented as green and red arrows, respectively; the inhibitory action of AKT on FOXO3a is represented with a dotted arrow since it is exerted only after oocyte activation. According to a current model, not illustrated in the figure, but reported in the test, signals from the microenvironment able to activate the PI3K/AKT/mTORC1 pathways in the pregranulosa cells reverse GO to the G1 stage and increment the production and release of factors, among these KL, which also incremented the PI3K/AKT/mTORC1 activity in the oocyte, leading to increased protein synthesis and removing the FOXO3a inhibition on its growth; in turn, the growing oocyte releases factors such as BMP15 and GDF9, which stimulate pregranulosa cell proliferation and their maturation into granulosa cells.