Infertility affects 15% of couples, with male factors implicated in half of all cases. Many male infertility phenotypes result from disrupted testis development. In addition, co-morbidities associated with male reproductive pathologies are often not diagnosed or their origins understood. To address this, our research has sought to delineate key steps and factors affecting mammalian testis development.
A well-established marker of low or absent sperm production in men is decreased circulating inhibin levels, a condition permissive for elevated bioactivity of activins, a known risk factor for cardiovascular disease and other pathologies. Human male siblings lacking a functional Inha gene are infertile, emphasising the importance of activin A bioactivity control in human fertility. Our studies of mouse models with no activin A (InhbaKO) and with unopposed/elevated activin A bioactivity (inhibin alpha subunit knockout: InhaKO) showed how activin A levels control somatic and germline testis cell development and functions in fetal, juvenile and adult life. This led us to identify the potential for activin A bioactivity to drive responses in fetal mouse testes and a human germ cell-derived cell line following exposure to endocrine disrupting chemicals.
Integration and control of TGFb superfamily signaling is essential for appropriate developmental outcomes across species. The network of shared signaling machinery ultimately relies on transcription factor access to the nucleus, which the importins, control.
This presentation will focus on our team’s discoveries relating to how male fertility is determined by the actions of the highly conserved Transforming Growth Factor-b (TGFb) superfamily signaling molecule, activin A, and by importins acting within germline cells.