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ICSI and the Discovery of the Sperm Factor and PLCζ1.

The discovery of PLCζ1 nearly twenty years ago as the primary Ca2+ oscillation inducing factor in the sperm of mammals represented a significant breakthrough in our quest to elucidate the molecules and pathways that promote egg activation during fertilization. The advent of the Intracytoplasmic Sperm Injection technique, which made fertilization possible without sperm capacitation, acrosome reaction, and gamete fusion, strengthened the research that led to the discovery of PLCζ1 and became an essential clinical tool for humans. The use of ICSI combined with the detection of PLCζ1 expression and mutations in infertile patients established the fundamental role of PLCζ1 in human fertility while leading to the discovery of novel components of the perinuclear theca, the site of the residence of PLCζ1 in sperm before fertilization. Remarkably, the more extensive use of ICSI in species other than humans and mice revealed poor success and exposed gaps in our understanding of PLCζ1 release and/or activation. Similarly, fertilization using sperm from mouse models lacking PLCζ1 has produced striking results whose true implications are yet to be determined. Nevertheless, answers to these unresolved questions will produce a complete picture of the adaptations and molecular players that mammalian species employ to ensure the success of the triggering event of embryo development that has linked generations since the beginning of times.