PRAMEL12 orchestrates spermiogenesis to ensure male fertility in mice

Spermiogenesis, the terminal phase of spermatogenesis, involves complex morphological and molecular changes essential for sperm maturation. While PRAMEL12, a cancer/testis antigen PRAME (preferentially expressed antigen of melanoma) family member, is implicated in spermatogenesis, its specific functions remain poorly understood. Here, global Pramel12 deletion in mice causes complete male infertility. Mutant males exhibit severe spermiogenesis defects, including impaired spermatid nuclear condensation, spermiation failure, and loss of sperm individualization. Consequently, sperm counts are drastically reduced, motility is severely impaired, and morphological abnormalities are markedly increased. Single-cell RNA-Seq reveals dysregulation of key genes governing sperm chromatin condensation and nuclear maturation in Pramel12-null spermatids. Proteomic profiling shows significant alterations in proteins essential for sperm structure, function, and manchette assembly. Critically, histochemical and protein profile analyses reveal a defective histone-to-protamine transition, characterized by aberrant histone modifications (including elevated H3K4me3, H3K9me3, H3K27me3, H3K23ac, and reduced H4K8ac), impaired TNP1/TNP2/PRM2 incorporation, and increased retention of core histones (H2A, H3, and H4) in mature sperm. Collectively, our findings establish PRAMEL12 as an essential regulator of spermiogenesis. Its deficiency disrupts histone-to-protamine exchange, causing abnormal sperm morphogenesis and functional defects that impair sperm quality and lead to male infertility. This identifies a novel mechanism for defective sperm chromatin condensation and male infertility.