Role of RNA modifications in spermatogenesis.

National Institute Of Environmental Health Sciences

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Abstract

Infertility affects approximately 10% of couples due to a combination of both male and female reproductive disorders. The proportion of infertile men and women is similar, but the etiology of the condition is sex-specific. The project aims to characterize molecular mechanisms required for sperm production. Genetic studies in rodents showed that several RNA binding proteins (RBPs) are necessary at different stages of gametogenesis; however, little is known about their functions mechanistically. We aim to gain insights into the role of RNA metabolism in sperm production by focusing on the role of RNA modifications. RBPs can promote transcript translation, storage, or degradation and is the balance between different protein complexes that decides the fate of the mRNA. In the process, the molecular machinery leaves various marks/modifications on the RNA that determine the molecular pathways the transcripts will follow. In particular, the 3 ends of mRNAs are tagged by specialized complexes that can sort the transcript into the different RNA processing compartments. The most common type of mRNA 3 end modification is the addition of a poly(A) tail. Several Terminal Nucleotidyl Transferases (TENTs) with polyadenylation potential are expressed during spermatogenesis. Some of these TENTs have been associated with male infertility, but the molecular mechanisms underlying these phenotypes remain poorly understood. Using a combination of advanced RNA detection methods and mouse models for TENTs, we identified key TENTs targets in germ cells. Future research will focus on an in-depth characterizing of the targeted pathways to gain mechanistic insights on how TENTs-depletion leads to infertility. This year, we also published a comprehensive review on RNA processing at every stage of spermatogenesis.