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Revealing RNA poly(A) tail dynamics during spermiogenesis and its function to support male fertility [dRNA-seq_mutants]

ABSTRACT: TENT5C is a terminal nucleotidyltransferase with mRNA polyadenylation activity, required for the fastening of the flagella and the head of the sperm. However, TENT5C’s role in shaping the poly(A) tail of the elongating spermatid transcriptome remains limited. Here we show that the poly(A) polymerase activity of TENT5C is required for fertility and spermiogenesis: male mice expressing catalytically inactive TENT5C (Tent5cdCat/dCat) are sterile and produce headless spermatozoa phenocopying TENT5C-deficient animals. We found that the transcript encoding for the structural proteins SMCP and ODF1 are directly targeted by TENT5C. We propose a model in which TENT5C secures the fastening of the flagella to the head of the sperm by targeting ODF1 in elongating spermatids.

ORGANISM(S): Mus musculus

PROVIDER: GSE290699 | GEO | 2025/03/20

REPOSITORIES: GEO

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Project description:Profilins (PFNs) are key regulatory proteins for the actin polymerization in cells and are encoded in mouse and humans by four Pfn genes. PFNs are involved in cell mobility, cell growth, neurogenesis and metastasis of tumor cells. The testis specific PFN3 is localized in the acroplaxome-manchette complex of developing sperm. We demonstrate, that PFN3 further localizes during spermiogenesis in the Golgi complex and proacrosomal vesicles, suggesting a role in acrosome formation. Autophagy is involved in proacrosomal vesicle fusion and transport to form the acrosome. Using CRISPR/Cas9 genome editing we generated mice deficient for Pfn3. Pfn3-/- males are sub-fertile displaying a type II-globozoospermia. We revealed, that Pfn3-/- sperm display abnormal manchette development leading to an amorphous sperm head shape. Additionally, Pfn3-/- sperm showed reduced sperm motility resulting from flagellum deformities. We show, that acrosome biogenesis is impaired starting from the Golgi phase. RNA-seq analysis revealed an upregulation of Trim27 and downregulation of Atg2a. As a consequence mTOR was activated and AMPK was suppressed resulting in the inhibition of autophagy. This dysregulation of AMPK/ mTOR affected the autophagic flux which is hallmarked by LC3B accumulation and increased SQSTM1 protein levels. We conclude that this disruption leads to the observed malformation of the acrosome. Further, actin related protein ARPM1 was absent in the nuclear fraction of Pfn3-/- testis and sperm. This suggests, that lack of PFN3 leads to destabilization of the stable PFN3-ARPM1 complex resulting in the degradation of ARPM1. Interestingly, in the Pfn3-/- testis, we detected increased protein levels of essential actin regulatory proteins, cofilin-1 (CFL1), cofilin-2 (CFL2) and actin depolymerizing factor (ADF). Taken together, our results reveal the importance for PFN3 in male fertility and implicates this protein as a candidate for male factor infertility in humans.

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Revealing RNA poly(A) tail dynamics during spermiogenesis and its function to support male fertility [dRNA-seq_mutants]

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