Regulation of Translational Suppression in Post-Meiotic Germ Cells: Crosstalk Between MicroRNAs and Actin-Associated Proteins.

Abstract

During male germ cell development, the vast majority of mRNAs is translationally repressed at the post-meiotic stage. While individual components implicated in the transcriptional and posttranscriptional control of specific germ cell gene expression have been identified, the mechanism that coordinates widespread translational suppression during germ cell differentiation remains unclear. In this study, we established that the cross-talk between miRNAs and actin-associated protein sets the tone for the mRNA-specific as well as general uncoupling of transcription and translation during post-meiotic germ cell maturation. Our study reveals that loss of the miRNA-processing enzyme Dicer function in haploid spermatids causes altered translational activation of several post-meiotic germ cell-specific transcripts, resulting in abnormal chromatin compaction and impaired fertility. We identified a specific miRNA-targeted actin-associated protein 2/3 complex (Arpc) subunit that plays a crucial role in this process as it sequesters germ cell-specific transcripts through their 3' UTR into translationally inert RNP complexes, and making them inaccessible to translational machinery. Interestingly, this actin-associated protein mediates translational suppression by interacting with GW182, a component of processing and chromatoid bodies, discrete cytoplasmic foci in the somatic and germ cells, respectively, believed to play an instrumental role in the storage and degradation of translationally suppressed mRNA. Collectively, our findings suggest that miRNAs are important checkpoint regulators that control timely expression of genes critical for post-meiotic germ cell differentiation and add a new dimension to the increasing role of actin and actin-associated proteins in post-transcriptional gene regulation. In light of recent studies showing an association between altered expression of actin-binding proteins and poor semen quality in human males, we propose that miRNA(s) targeting this Arpc subunit may serve as novel biomarkers for defective sperm and impaired male fertility. This research is funded by the NIH (HD053774-03). (platform)