Age-dependent alterations in spermatogenesis in itchy mice

Spermatogenesis is an intricate process in which spermatogonial stem cells divide and differentiate to produce mature sperm. This process strongly depends on protein turnover both in the developing germ cells and the supportive Sertoli cells, and recent evidence has demonstrated the role of the ubiquitin-proteasome system in this protein turnover in the testis. Itch, an E3 ligase important in the immune system, has been implicated in regulating the blood testis barrier. Although the specific role of Itch during spermatogenesis is not yet well understood, its ubiquitous expression and wide array of functional targets suggest multiple and tissue-specific roles. Here the testes of mice that lack Itch protein are evaluated at two developmental time points: peri-pubertal postnatal day (PND) 28 and adult PND 56. Itchy mice demonstrate an increased germ cell apoptotic index compared with wild type C57BL/6J mice at both PND 28 and PND 56. A corresponding 27% reduction in the total number of spermatid heads produced in PND 56 itchy mice was also evident. A histological evaluation of itchy mice revealed a delay in spermatogenesis at PND 28 and disorganization of late stage spermatids at PND 56. An analysis of several apoptotic markers revealed an age-dependent change in cleaved caspase 9, an intrinsic apoptosis mediator. The breeding success of the itchy mice was also significantly decreased, possibly due to a developmental defect. Taken together, these findings indicate that Itch is required for functional spermatogenesis, and that it may play differing cellular roles during development.