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Phospholipase Cζ rescues failed oocyte activation in a prototype of male factor infertility
Michail Nomikos1, Yuansong Yu2, Khalil Elgmati2
1Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom; National Center for Scientific Research "Demokritos," Aghia Paraskevi, Greece.
Objective:
To determine the effect of infertility-linked sperm phospholipase Cζ (PLCζ) mutations on their ability to trigger oocyte Ca(2+) oscillations and development, and also to evaluate the potential therapeutic utility of wild-type, recombinant PLCζ protein for rescuing failed oocyte activation and embryo development.
Design:
Test of a novel therapeutic approach to male factor infertility.
Setting:
University medical school research laboratory.
Patient(S):
Donated unfertilized human oocytes from follicle reduction.
Intervention(S):
Microinjection of oocytes with recombinant human PLCζ protein or PLCζ cRNA and a Ca(2+)-sensitive fluorescent dye.
Main Outcome Measure(S):
Measurement of the efficacy of mutant and wild-type PLCζ-mediated enzyme activity, oocyte Ca(2+) oscillations, activation, and early embryo development.
Result(S):
In contrast to the wild-type protein, mutant forms of human sperm PLCζ display aberrant enzyme activity and a total failure to activate unfertilized oocytes. Subsequent microinjection of recombinant human PLCζ protein reliably triggers the characteristic pattern of cytoplasmic Ca(2+) oscillations at fertilization, which are required for normal oocyte activation and successful embryo development to the blastocyst stage.
Conclusion(S):
Dysfunctional sperm PLCζ cannot trigger oocyte activation and results in male factor infertility, so a potential therapeutic approach is oocyte microinjection of active, wild-type PLCζ protein. We have demonstrated that recombinant human PLCζ can phenotypically rescue failed activation in oocytes that express dysfunctional PLCζ, and that this intervention culminates in efficient blastocyst formation.
Insights
Mutations in sperm phospholipase Cζ (PLCζ) cause male infertility by preventing oocyte activation. Recombinant PLCζ protein can rescue this failure, enabling successful embryo development to the blastocyst stage.
Area of Science:
- Reproductive Biology
- Molecular Biology
- Infertility Research
Background:
- Sperm phospholipase Cζ (PLCζ) is crucial for initiating oocyte activation during fertilization.
- Mutations in PLCζ are linked to male factor infertility due to failed oocyte activation.
- Understanding PLCζ function is key to developing new infertility treatments.
Purpose of the Study:
- To investigate the impact of infertility-linked PLCζ mutations on oocyte activation and development.
- To assess the therapeutic potential of wild-type recombinant PLCζ protein for treating failed oocyte activation.
Main Methods:
- Microinjection of unfertilized human oocytes with mutant or wild-type PLCζ protein/cRNA.
- Utilized a Ca(2+)-sensitive fluorescent dye to measure oocyte calcium oscillations.
- Assessed oocyte activation and subsequent early embryo development to the blastocyst stage.
Main Results:
- Mutant human sperm PLCζ exhibited aberrant enzyme activity and failed to trigger oocyte activation.
- Wild-type recombinant PLCζ protein successfully induced characteristic Ca(2+) oscillations, essential for oocyte activation.
- Microinjection of recombinant PLCζ led to successful embryo development to the blastocyst stage.
Conclusions:
- Dysfunctional sperm PLCζ is a cause of male factor infertility.
- Oocyte microinjection with active, wild-type PLCζ protein represents a potential therapeutic strategy.
- Recombinant human PLCζ can rescue failed oocyte activation, leading to efficient blastocyst formation.
