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Ccdc117 deficiency triggers compensatory hyperandrogenism to sustain spermatogenesis and male fertility

ABSTRACT: Background The precise regulation of testicular steroidogenesis is fundamental to male fertility. While many coiled-coil domain-containing (CCDC) proteins are critical structural components of spermatogenesis, the functional role of the testis-enriched CCDC117 remains undefined, presenting a significant gap in our understanding of local testicular regulation. Methods We generated a Ccdc117 knockout mouse model using CRISPR/Cas9 and characterized the phenotypic consequences through histology, computer-assisted sperm analysis (CASA), and fertility assessments. The molecular underpinnings were investigated via testis-wide RNA sequencing, Western blotting, immunofluorescence, and hormonal measurements. Results Ccdc117ko males developed a paradoxical phenotype: significant testicular hypotrophy alongside completely preserved fertility. Despite a ~25% reduction in testis size, sperm counts, motility, and spermatogenic progression were normal. Transcriptomic analysis uncovered a specific and coordinated upregulation of the steroidogenic pathway, which was validated by a concomitant increase in the protein levels of key enzymes (CYP17A1, StAR, HSD3B2) specifically within Leydig cells. Consequently, serum testosterone levels were significantly elevated by approximately two-fold without a concomitant rise in GnRH.

ORGANISM(S): Mus musculus

PROVIDER: GSE311763 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:The specific role of polyamines in the testis physiology is not fully understood. Antizymes (OAZs) and antizyme inhibitors (AZINs) are modulators of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis and polyamine uptake. Although the three known OAZs are expressed in the testis, only OAZ3 is testis specific and has been proven to have an essential role in male fertility. Regarding the two existing AZINs, AZIN2 is the most abundantly expressed member in this gonad. Whereas previous studies suggested that AZIN2 might participate in mouse spermatogenesis, immunohistological analysis of human testicular sections revealed that AZIN2 is also detected in the steroidogenic Leydig cells but not in the germinal epithelium. In the present study, we found a close ontogenic similarity in the mRNA levels of OAZs and AZINs between mice and rats, but an opposite expression pattern of ODC activity. Further analysis of AZIN2 and OAZ3 in the testis of mice with different alterations in spermatogenesis and fertility, induced either genetically or pharmacologically, corroborated that both AZIN2 and OAZ3 are mainly expressed in the haploid germinal cells. Finally, by using transgenic mice with a truncated Azin2 gene fused to the bacterial lacZ gene, we studied the expression of Azin2 in testes, epididymides and spermatozoa. AZIN2 was detected in spermatids and spermatozoa, as well as in Leydig cells, and in epithelial epidydimal cells. Azin2 knock-out male mice were fertile; however, they showed marked decreases in testicular putrescine and plasma and testicular testosterone levels, and a dramatic reduction in the sperm motility. These results suggest an important role for AZIN2 in testicular cells by modulating polyamine concentrations, testosterone synthesis and sperm function. Overall, our data corroborate the relevance of polyamine regulation in spermatogenesis, where both AZIN2 and OAZ3 play fundamental roles. We used microarrays in order to detect how the disruption of Azin2 could affect overall gene expression in testis.

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Ccdc117 deficiency triggers compensatory hyperandrogenism to sustain spermatogenesis and male fertility

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