The evolutionarily conserved gene Arrdc5 is required for male fertility

Abstract In sexually reproducing organisms, sperm contribute half the genomic material required for creation of offspring and natural fertility relies on males producing millions by way of spermatogenesis. This process is essential for continuity and diversity of a species, yet evolutionarily conserved core molecular regulators are undefined. Here we used single cell RNA-sequencing of testicular tissue from mice, pigs, and cattle to generate a multispecies integrated transcriptome database. Through bioinformatic analysis, the gene arrestin-domain containing 5 (Arrdc5) which encodes for an α-arrestin molecule was identified as a potential evolutionarily conserved regulator of spermatogenesis. Expression of Arrdc5 is testis specific in mice, pigs, cattle, and humans. Knockout of Arrdc5 in mice leads to male specific sterility due to production of low numbers of sperm that are immotile and malformed, resembling oligoasthenoteratospermia (OAT) which is a common diagnosis of infertility in men. Spermiogenesis, the final phase of spermatogenesis when round spermatids morphologically transform to spermatozoa, is defective in testes of Arrdc5 deficient mice. Also, epididymal sperm in Arrdc5 knockouts are unable to capacitate and fertilize oocytes. These findings establish ARRDC5 as a core regulator of mammalian spermatogenesis. Considering the role of arrestin molecules as modulators of G-protein coupled signaling and ubiquitination, ARRDC5 is a potential male contraceptive target.