Regulated Wnt/beta-catenin signalling is intrinsically required for adult spermatogenesis (#47)
Male infertility is a worldwide health problem with increasing incidence. The importance of Wnt signalling in postnatal testis function has been studied in several mouse models with chronic pathway disruption, addressing its function in Sertoli cells and in post-meiotic germ cells. While chronic β-catenin deletion in Sertoli cells does not profoundly affect the testis, emerging data indicates that Wnt signalling functions at multiple stages of spermatogenesis. We have used two mouse models with acute disruption of Wnt signalling to explore the importance of regulated Wnt pathway activity for normal germ cell development in adult male mice. Short term induction of mutations, in Apc and β-catenin, that increase and decrease Wnt signalling levels, respectively, have been generated in AhCre Apcflox/flox and AhCre β-catflox/flox mice. Both exhibited phenotypes of disrupted spermatogenesis that are distinguishable within 24 hours and which persist for up to 4 days. This pathway disruption leads to rapid germ cell loss, apoptosis and perturbations in Sertoli cell morphology that correspond to altered distribution of the blood testis barrier protein, connexin 43. The loss of predominantly post-mitotic germ cells in both models is in accord with detection of nuclear β-catenin protein in spermatocytes and round spermatids, indicative of active Wnt signalling. Our transcriptional profiling of wild type postnatal mouse testes has identified a cohort of developmentally regulated transcripts encoding Wnt receptors (e.g. Fzd4) and ligands (e.g. Wnt3, Wnt3a, Wnt5b, Wnt7a and Wnt8b), while examination of selected transcripts in AhCre β-catflox/flox mutant testes match their deduced localization to post-mitotic cells. These findings demonstrate that intrinsic control of Wnt signalling in germ cells is essential for adult spermatogenesis, while its disruption may underpin some cases of male infertility.