Dataset Information

Loss of Cep70 function affects acrosome biogenesis and flagella formation during spermiogenesis

ABSTRACT: The spermatogenesis process is complex and delicate, and any error in any step may cause spermatogenesis arrested and even male infertility. Through mutation screening of patients with clinical azoospermia, we found a heterozygous site of the same mutation on CEP70. The centrosome protein 70 (Cep70) is involved in the regulation of microtubule assembly and shows a high expression trend during human spermatogenesis, but the specific mechanism of this protein in spermatogenesis is still unknown. Therefore, we deleted Cep70 in mice and founded that the deletion of Cep70 causes abnormal spermatogenesis and leads to male sterility. We found that knockout of Cep70 did not affect the prophase of meiosis I, but led to higher levels of thyroid hormone secretion, male germ cell apoptosis and abnormal spermiogenesis. By TEM and SEM analysis, we found that deletion of Cep70 results in abnormal formation of flagella and acrosome during spermiogenesis. TMT-labeled quantitative proteomic analysis revealed that the absence of Cep70 led to the significantly decrease of proteins associated with the formation of the flagella, head and acrosome of sperm and microtubule cytoskeleton according to the proteomic data. Taken together, our results show that Cep70 is essential for the acrosome biogenesis and flagella formation during spermiogenesis.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: Qiang Liu

LAB HEAD: Qiang Liu

PROVIDER: PXD023680 | Pride | 2021-09-10

REPOSITORIES: Pride

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Publications

Loss of CEP70 function affects acrosome biogenesis and flagella formation during spermiogenesis.

Liu Qiang Q Guo Qianying Q Guo Wei W Song Shi S Wang Nan N Chen Xi X Sun Andi A Yan Liying L Qiao Jie J

Cell death & disease 20210512 5

The spermatogenesis process is complex and delicate, and any error in a step may cause spermatogenesis arrest and even male infertility. According to our previous transcriptomic data, CEP70 is highly expressed throughout various stages of human spermatogenesis, especially during the meiosis and deformation stages. CEP70 is present in sperm tails and that it exists in centrosomes as revealed by human centrosome proteomics. However, the specific mechanism of this protein in spermatogenesis is stil ...[more]

PMID: 33980814

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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.

Dataset Information

Loss of Cep70 function affects acrosome biogenesis and flagella formation during spermiogenesis

Publications

Loss of CEP70 function affects acrosome biogenesis and flagella formation during spermiogenesis.

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