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Abstract Septins are a family of cytokinesis-related proteins involved in regulating cytoskeletal design, cell morphology, and tissue morphogenesis. Apart from cytokinesis, as a fourth component of cytoskeleton, septins aid in forming scaffolds, vesicle sorting and membrane stability. They are also known to be involved in the regulation of intracellular calcium (Ca2+) via the STIM/Orai complex. Infertility affects ~ 15% of couples globally, while male infertility affects ~ 7% of men. Global pregnancy and live birth rates following fertility treatment remain relatively low, while there has been an observable decline in male fertility parameters over the past 60 years. Low fertility treatment success can be attributed to poor embryonic development, poor sperm parameters and fertilisation defects. While studies from the past few years have provided evidence for the role of septins in fertility related processes, the functional role of septins and its related complexes in cellular processes such as oocyte activation, fertilization, and sperm maturation are not completely understood. This review summarizes the available knowledge on the role of septins in spermatogenesis and oocyte activation via Ca2+ regulation, and cytoskeletal dynamics throughout pre-implantation embryonic development. We aim to identify the currently less known mechanisms by which septins regulate these immensely important mechanisms with a view of identifying areas of investigation that would benefit our understanding of cell and reproductive biology, but also provide potential avenues to improve current methods of fertility treatment.

Oocyte activation, a fundamental event during mammalian fertilisation, is initiated by concerted intracellular patterns of calcium (Ca2+) release, termed Ca2+ oscillations, predominantly driven by testis-specific phospholipase C zeta (PLCζ). Ca2+ exerts a pivotal role in not just regulating oocyte activation and driving fertilisation, but also in influencing the quality of embryogenesis. In humans, a failure of Ca2+ release, or defects in related mechanisms, have been reported to result in infertility. Furthermore, mutations in the PLCζ gene and abnormalities in sperm PLCζ protein and RNA, have been strongly associated with forms of male infertility where oocyte activation is deficient. Concurrently, specific patterns and profiles of PLCζ in human sperm have been linked to parameters of semen quality, suggesting the potential for PLCζ as a powerful target for both therapeutics and diagnostics of human fertility. However, further to PLCζ and given the strong role played by Ca2+ in fertilisation, targets down- and up-stream of this process may also present a significantly similar level of promise. Herein, we systematically summarise recent advancements and controversies in the field to update expanding clinical associations between Ca2+-release, PLCζ, oocyte activation and human fertility. We discuss how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic avenues presented by oocyte activation for the diagnosis and treatment of human infertility.