Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility.

Spermatogenesis in mammals necessitates an extensive remodeling and loss of many cellular organelles and proteins as the spermatozoa undergo maturation. The removal of proteins and organelles depends on the ubiquitin-proteasome pathway. Here we show that the E3 ubiquitin ligase Herc4, though ubiquitously expressed in all tissues, is most highly expressed in the testis, specifically during spermiogenesis. Mice homozygous for a Herc4 mutation are overtly normal; however, overall the males produce litter sizes some 50% smaller whereas female homozygotes show normal fertility. The reduced fertility in males is associated with about 50% of mature spermatozoa having reduced motility. Many of the spermatozoa possess an angulated tail with a cytoplasmic droplet being retained at the angulation. Our results show that Herc4 ligase is required for proper maturation and removal of the cytoplasmic droplet for the spermatozoon to become fully functional.