The Role Of Raptor In Regulating Meiosis And Meiotic Sex Chromosome Inactivation

Rapamycin is a clinically important drug used in transplantation and cancer therapy,but causes a number of side effects,including male infertility.The target of rapamycin-mTOR is a central regulator of cellular metabolic,it forms two distinct multiprotein complexes mTORC1 and mTORC2 to execute its functions.It plays a critical role in many cellular progression,such as biosynthesis of proteins,glucose metabolism and actin cytoskeleton organization.These cellular function are also pivotal to spermatogenesis.Meiosis is a specialized division process in germ cells,and is crucial to spermatogenesis.Key stages in meiosis include chromosomal pairing,chromosomal synapsis(alignment),recombination and meiotic sex chromosome inactivation(MSCI).Defects in these stages often lead to meiotic arrest and disrupt spermatogenesis.However,the molecular mechanisms by which mTOR signaling acts in male meiosis are still not fully understood.To explore the function of mTOR signaling in spermatogenesis and male meiosis,we generated germline specific knock out of Raptor by crossing mice carrying a floxed allele of Raptor with mice expressing Ngn3-Cre.We found that disruption of the Raptor gene caused meiosis arrest at pachytene stage.Further study revealed that chromosomal synapsis and meiotic sex chromosome inactivation were impaired.Taken together,these results demonstrate that mTORC1 has an essential role in meiotic progression and silencing of sex chromosomes in the male germ line,which not only helps to better understand of the infertility associated with mTOR inhibitors such as rapamycin,but also provides the fundamental basis for developing male contraceptives by manipulating mTORC1 signaling in the future.