Signaling Pathways Regulating Cyst Breakdown, Primordial Follicle Formation, and Meiotic Progression in the Mouse Ovary

Date of Award

Summer 8-27-2021

Degree Type


Degree Name

Doctor of Philosophy (PhD)




Pepling, Melissa


Cyst Breakdown, PI3K Signaling, Primordial Follicle Formation

Subject Categories

Biochemistry, Biophysics, and Structural Biology | Biology | Cell and Developmental Biology | Developmental Biology | Life Sciences | Molecular Biology


Normative fecundity in mammalian females is linked to the robust function of the receptor tyrosine kinase, KIT. Intracellular signal transduction mediated by KIT is important for developmental processes such as oogenesis and folliculogenesis, which are key determinants of the size and quality of the ovarian reserve as well as the subsequent maturation of 'eggs' for reproductive use. Establishment of the ovarian reserve involves the breakdown of germ cell cysts, formation of primordial follicles, and the progression of oocytes through the first meiotic prophase. Although KIT signaling is known to modulate the ovarian reserve, the mechanisms downstream of the receptor are not thoroughly understood. The primary focus of this dissertation was to elucidate how KIT regulates the ovarian reserve by investigating the downstream signaling cascades involved in germ cell cyst breakdown, primordial follicle formation, and meiotic progression. Using an ovary culture system, we found that KIT activated the phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling pathways by inducing p-AKT and p-MAPK3/1 when ovaries were supplemented with KIT ligand (KITL). Activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway via induction of p-STAT3 was not observed in response to KITL supplementation. Our histological analyses of ovaries cultured with the PI3K inhibitor LY294002, or the MAPK3/1 inhibitor U0126, confirmed that both cascades promote oocyte growth and follicle development. Interestingly, we uncovered that cyst breakdown and primordial follicle formation were not perturbed by the inhibition of MAPK3/1 but were delayed by the inhibition of PI3K. The delay in cyst breakdown was mitigated when ovaries were dually dosed with LY294002 and KITL, suggesting that while KIT may signal through PI3K to promote cyst breakdown, other signaling networks downstream of the receptor could compensate. Additionally, our results demonstrate that KIT, MAPK3/1, and PI3K signaling contribute to meiotic progression in oocytes. Overall, our data have provided new insights into the role of PI3K signaling in the establishment of the ovarian reserve and suggest that PI3K might be the primary mediator of KIT-induced cyst breakdown and primordial follicle formation in the mouse ovary.


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