Characterization of the Role of Tumor Necrosis Factor Apoptosis Inducing Ligand (TRAIL) in Spermatogenesis through the Evaluation of Trail Gene-Deficient Mice

TRAIL (TNFSF10/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily of proteins and is expressed in human and rodent testis. Although the functional role of TRAIL in spermatogenesis is not known, TRAIL is recognized to induce apoptosis via binding to its cognate receptors; DR4 (TRAIL-R1/TNFRSF10A) and DR5 (TRAIL-R2/TNFRSF10B). Here, we utilize Trail gene-deficient (Trail(-/-)) mice to evaluate the role of TRAIL in spermatogenesis by measuring testis weight, germ cell apoptosis, and spermatid head count at postnatal day (PND) 28 (pubertal) and PND 56 (adult). Trail(-/-) mice have significantly reduced testis to body weight ratios as compared to wild-type C57BL/6J at both ages. Also, Trail(-/-) mice (PND 28) show a dramatic increase in basal germ cell apoptotic index (AI, 16.77) as compared to C57BL/6J (3.5). In the testis of adult C57BL/6J mice, the AI was lower than in PND 28 C57BL/6J mice (2.2). However, in adult Trail(-/-) mice, the AI was still higher than that of controls (9.0); indicating a relative high incidence of germ cell apoptosis. Expression of cleaved caspase-8 (CC8) and cleaved caspase-9 (CC9) (markers of the extrinsic and intrinsic apoptotic pathway, respectively) revealed a twofold increase in the activity of both pathways in adult Trail(-/-) mice compared to C57BL/6J. Spermatid head counts in adult Trail(-/-) mice were dramatically reduced by 54% compared to C57BL/6J, indicating these animals suffer a marked decline in the production of mature spermatozoa. Taken together, these findings indicate that TRAIL is an important signaling molecule for maintaining germ cell homeostasis and functional spermatogenesis in the testis.