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This study identifies two phospholipase C enzymes, PLCζ1 and PLCδ4, that work together to trigger the calcium oscillations necessary for egg activation during fertilization in mice. While PLCζ1 is the primary trigger, researchers found that PLCδ4 serves as a compensatory mechanism, and male mice lacking both enzymes are completely sterile because their sperm cannot induce the calcium signals required for fertilization. The research demonstrates that mammalian fertilization relies on a multi-component system rather than a single molecule.
Why it matters
These findings could help diagnose and potentially treat certain cases of male infertility linked to defective calcium signaling at fertilization. The research also has implications for improving assisted reproductive technologies like IVF and could inform the development of new contraceptive approaches targeting these specific enzymes.
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by Neha Gupta, Lei Zhang, Hiroki Akizawa, Maria G. Gervasi, Darya A. Tourzani, Pablo E. Visconti, Ana Romarowski, Mariano Buffone, Wei Cui, Rafael A. Fissore
Fertilization-induced calcium (Ca2+) oscillations are essential for egg activation and embryonic development in mammals. The sperm-specific phospholipase C isoform, PLCζ1, is the primary trigger of these oscillations. Functional and clinical studies have linked mutations or reduced expression of PLCζ1 to male infertility. However, whether PLCζ1 alone accounts for Ca2+ release at fertilization in all mammals remains uncertain. Male mice lacking Plcζ1 exhibit subfertility and reduced litter sizes; their sperm induce delayed, low-frequency Ca2+ oscillations, indicating a compensatory mechanism. Notably, mouse sperm express high levels of PLCδ4, essential for completing the acrosome reaction (AR). In Plcζ1-null sperm, PLCδ4 is upregulated and retained post-AR. These observations suggest a secondary functional role for PLCδ4. Using CRISPR/Cas9 genome editing, we generated Plcδ4 knockout (KO) mice. Plcδ4-null sperm trigger attenuated, delayed Ca2+ oscillations and significantly reduced fertilization rates, indicating that PLCδ4 contributes to but does not independently drive Ca2+ signaling. We therefore generated a Double Knockout (DKO) mouse line lacking both sperm-enriched PLCs. DKO males were sterile, with sperm failing to induce Ca2+ oscillations, and the isolated residual Ca2+ rise was insufficient to activate eggs. These findings reveal that PLCζ1, the primary oscillator, and PLCδ4, a compensatory factor, work cooperatively within a complex, multi-component PLC system that ensures robust fertilization. This work reveals molecular specialization among mammals in initiating the fertilization Ca2+ signals. It has implications for understanding male infertility, improving assisted reproductive technologies, and developing contraceptive strategies.