Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice.

Fan Diao,Chen Jiang,Bing Yao,Qiang Wang,Chao-Jun Li,Rui-Lou Zhu,Xiu-Xing Wang

doi:10.1038/srep28917

Abstract

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.

Highlights

Decreased after postnatal day 9, and continued to decrease as age increased[10]
These data indicated that Ggpps deletion in germ cells resulted in germ cell loss and seminiferous tubule degeneration, which led to male infertility
We showed that the protein prenylation balance takes part in spermatogonial differentiation of newborn mice

Summary

Introduction

Decreased after postnatal day 9, and continued to decrease as age increased[10]. Protein prenylation, including farnesylation and geranylgeranylation, is an important protein modification that can covalently attach either a farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP) to conserved cysteine residues at or near the C-terminus of particular proteins[11]. Our study of male infertility patients who had been infected with the mumps virus before puberty, altered prenylation levels caused by Ggpps deficiency in Sertoli cells induced excessive cytokine and chemokine synthesis and secretion, which resulted in spermatogonia apoptosis and subsequent infertility in adult mice[13] These findings suggest that protein prenylation in the seminiferous epithelium is crucial in early stage of spermatogenesis before sexual maturity. Elevated Rheb farnesylation subsequently activated mTORC1 signaling and induced cardiomyocyte hypertrophy, cardiac fibrosis and excessive apoptosis, eventually led to severe heart failure[26] In light of these findings, we hypothesized that prenylation of the small GTPase might play a particular role in spermatogenesis within germ cells. Mechanistic studies further proved that protein farnesylation levels contributed to spermatogonial differentiation mediated by the Rheb-activated mTORC1 pathway

Methods

Results

Conclusion