Loss of GGPPS from childhood mumps infection or deletion in mice results in constitutively activated MAPK and NF-kB signaling that induces spermatogonium apoptosis, macrophage invasion into seminiferous tubules, and sterility.

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.

Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The stage-dependent changes in protein prenylation in the seminiferous epithelium might be important during the first round of spermatogenesis before sexual maturation, but the mechanisms are unclear. We have previous found that altered prenylation in Sertoli cells induced spermatogonial apoptosis in the neonatal testis, resulting in adult infertility. Now we further explored the role of protein prenylation in germ cells, using a conditional deletion of geranylgeranyl diphosphate synthase (Ggpps) in embryonic stage and postmeiotic stage respectively. We observed infertility of Ggpps−/− Ddx4-Cre mice that displayed a Sertoli-cell-only syndrome phenotype, which resulted from abnormal spermatogonial differentiation and SSC depletion during the prepubertal stage. Analysis of morphological characteristics and cell-specific markers revealed that spermatogonial differentiation was enhanced from as early as the 7th postnatal day in the first round of spermatogenesis. Studies of the molecular mechanisms indicated that Ggpps deletion enhanced Rheb farnesylation, which subsequently activated mTORC1 and facilitated spermatogonial differentiation. In conclusion, the prenylation balance in germ cells is crucial for spermatogonial differentiation fate decision during the prepubertal stage, and the disruption of this process results in primary infertility.

Mumps commonly affects children 5-9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell-only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients' fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-B signaling pathways were constitutively activated in GGPPS / Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS / Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.

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