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The molecular basis for the ability of PLC zeta to stimulate mammalian embryo development

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Factors of male infertility

Infertility affects one in seven couples worldwide. Understanding the biology behind mammalian fertilisation is central to providing adequate solutions.

Fundamental Research

Oocyte activation is the earliest step of embryonic development following mammalian fertilisation. It is triggered by calcium oscillations, which are initiated by a sperm-specific protein factor, termed PLC zeta. Calcium oscillations may directly influence the efficacy of embryo development and underlie the drastically low success rates of current fertility treatments. The EU-funded ZETA-STIM (The molecular basis for the ability of PLC zeta to stimulate mammalian embryo development) project investigated the molecular mechanism of mammalian fertilisation focusing on the determinant factors of calcium oscillations. They demonstrated that sperm PLC zeta is the sole factor responsible for the generation of calcium oscillations during mammalian fertilisation. In addition, they showed that the domain-binding sperm protein PAWP was unable to elicit calcium oscillations in mouse and human oocytes. PAWP had been recently proposed as an alternative molecule that is responsible for oocyte activation. Pre-clinical data demonstrated that recombinant human PLC zeta could rescue failed oocyte activation in a mouse model of male infertility. These results clearly indicated that PLC zeta could serve as a therapeutic agent to overcome certain forms of male infertility. Towards this goal, scientists developed various protocols to produce recombinant human PLC zeta that can be used from IVF clinics. Researchers also provided insight into the biochemical structure of PLC zeta and delineated its catalytic domain. A recent report showed that a point mutation in PLC zeta C2 domain was associated with oocyte activation failure. This observation underscored the vital role of this domain in PLC zeta function and triggered ZETA-STIM scientists to perform biochemical and biophysical analysis of the C2 domain to deduce its binding to various oocyte proteins. Collectively, the findings of the project provide unprecedented evidence on the function of PLC zeta. Although the precise mechanism of function of PLC zeta is still not clear, the study opened new avenues for the therapy of male infertility.


Infertility, oocyte activation, calcium oscillation, PLC zeta, ZETA-STIM

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