DIS3 ribonuclease regulates Sertoli cell development to support spermatogenesis in mice.

While DIS3 functions in male germ cells are emerging, its ribonuclease activity governing Sertoli cell RNA metabolism, essential for testicular development and spermatogenesis, remains undefined. This study identifies a crucial role for exosome-associated DIS3 ribonuclease in regulating Sertoli cell maintenance and maturation during spermatogenesis. Dis3 deficiency in Sertoli cells causes severe testicular atrophy, marked by rapid depletion of both Sertoli and germ cells. This phenotype results from impaired Sertoli cell proliferation, elevated apoptosis, disrupted maturation, and compromised blood-testis barrier integrity, culminating in defective spermatogenesis and infertility. Single-cell RNA-sequencing analysis reveals altered cell-cell communication, alongside heightened p53 and Wnt signaling activity in Dis3 conditional knockout Sertoli cells. p53 inhibitor treatment mitigates overt apoptosis in Dis3 conditional knockout Sertoli cells. Similarly, inhibition of the Wnt/β-catenin pathway increases the abundance of both Sertoli and germ cells while improving Sertoli cell maturation. Together, these findings establish Sertoli cell-specific DIS3 as essential for testicular development and spermatogenesis in mouse, and implicate the p53 and Wnt/β-catenin pathways as potential mechanistic contributors.