GGPP-Mediated Protein Geranylgeranylation in Oocyte Is Essential for the Establishment of Oocyte-Granulosa Cell Communication and Primary-Secondary Follicle Transition in Mouse Ovary

Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown. Here, we report that oocyte geranylgeranyl diphosphate (GGPP), a metabolic intermediate involved in protein geranylgeranylation, is required to establish the oocyte-granulosa cell communication. GGPP and geranylgeranyl diphosphate synthase (Ggpps) levels in oocytes increased during early follicular development. The selective depletion of GGPP in mouse oocytes impaired the proliferation of granulosa cells, primary-secondary follicle transition and female fertility. Mechanistically, GGPP depletion inhibited Rho GTPase geranylgeranylation and its GTPase activity, which was responsible for the accumulation of cell junction proteins in the oocyte cytoplasm and the failure to maintain physical connection between oocyte and granulosa cells. GGPP ablation also blocked Rab27a geranylgeranylation, which might account for the impaired secretion of oocyte materials such as Gdf9. Moreover, GGPP administration restored the defects in oocyte-granulosa cell contact, granulosa cell proliferation and primary-secondary follicle transition in Ggpps depletion mice. Our study provides the evidence that GGPP-mediated protein geranylgeranylation contributes to the establishment of oocyte-granulosa cell communication and then regulates the primary-secondary follicle transition, a key phase of folliculogenesis essential for female reproductive function.
Author Summary Folliculogenesis is a progressive and highly regulated process that requires the tight coordination of metabolism and bidirectional communication between the oocyte and granulosa cells. How this communication is established remains unclear. Here, we find that GGPP-mediated protein geranylgeranylation, a post-translational modification, is essential for the oocyte-granulosa cell communication. GGPP depletion in oocytes inhibits Rho GTPase geranylgeranylation-regulated cell adhesion and impairs Rab GTPase geranylgeranylation-directed cell secretion, which are responsible for the failure to maintain oocyte-granulosa cell communication. This communication defect is probably not able to support the proliferation of granulosa cells from one layer to multiple layers and ultimately results in the failure of the primary-secondary follicle transition and female subfertility. Our findings provide the evidence of GGPP-mediated protein geranylgeranylation involving in regulating primary-secondary follicle transition and establish a novel link between folliculogenesis and GGPP-regulated membrane dynamics.