Of mice and men: translating mouse knockout models of human male infertility

Infertility is a global health issue affecting a significant portion of couples, estimated at ∼10-15% of reproductive-aged couples worldwide, with the World Health Organisation (WHO) suggesting roughly one in six (∼17.5%) of the adult population experiences infertility. Male causes of infertility are attributable as a sole or leading cause in 40-50% of cases. Furthermore, sperm/semen counts have plummeted by ∼60% over the past 50-60 years in males attending fertility clinics. There is thus an urgent need to understand the causes behind these numbers to address such worrying trends. However, human male infertility is a heterogeneous and often idiopathic condition, with genetic factors increasingly recognised as major contributors. In this review, we examine known and emerging genetic causes of male infertility, highlighting how knockout mouse models have been leveraged to understand not only male reproductive biology and sperm physiological function, but also to illustrate how specific genetic disruptions correspond to particular reproductive failures, discussing how such mouse models are illuminating the causes of human idiopathic male infertility and guiding the discovery of novel infertility genes. We compare the similarities and differences between human and mouse infertility, not only identifying areas of further investigation that require urgent attention, but also potential novel avenues of therapeutic treatment.