Identification of protein facilitating  gamete fusion

Gamete fusion is the union of two haploid cells (sperm and egg) resulting in fertilisation and embryo development. In mice, this fundamental process is depended on the presence of the egg receptor on the sperm membrane (IZUMO1) and the sperm receptor on the egg membrane (JUNO). While the relevance of this sperm-egg receptors interaction is well-known and conserved across mammals, other receptors on the sperm membrane seem to also play a key role in gamete fusion by interacting with IZUMO1 in the gamete fusion (e.g. DCST1, DCST2, FIMP, TMEM95, and SPACA6). Despite of that, the molecular interactions involved in gamete fusion are frequently overlooked in the clinical practice, and many couples attempting to conceive are often diagnosed with unexplained infertility. In this regard, the article highlighted herein provides evidence of the involvement of a new protein in gamete fusion.

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An international research team at the University of Sheffield used a functionally coated 3D microsphere-system mimicking oocytes to identify new human sperm-egg fusion proteins. Vondrakova and colleagues demonstrated that ≤1 in 1000 beads bound to sperm and identified MAIA (named after the Greek goddess of motherhood) as promising candidate. To study the role of MAIA in gamete fusion, they transfected the MAIA coding gene (FcRL3) and JUNO-carrying plasmid into hamster eggs and incubated them with capacitated sperm.

They further observed that the transfected eggs not only showed increased sperm adherence, presence of sperm nuclei in the egg cytoplasm but also overexpressed MAIA and JUNO. All representing hallmarks of cell- cell fusion. In addition to using non-human eggs, the team also performed trasfections of the construct into humans embryonic kidneys cells, which were also incubated with capacitated sperm. The team observed fusion between the two cell types, which would not otherwise fuse in a normal scenario, supporting the role of MAIA in the sperm binding process.

In summary, these in vitro experiments allowed the identification of MAIA as a key sperm receptor on the egg membrane essential for human gamete fusion in the presence of JUNO. The homology of FcRL3 across taxa is variable, and therefore indicates species specificity. Studies with mouse models also suggest that genes in the FcRL family may play a role in reproductive processes. In addition, identification of the molecular interactions of gamete fusion might also explain certain cases of ‘unexplained infertility’. In particularly, the MAIA receptor might explain why in humans some sperm are non compatible with the partner’s eggs. Such discovery represents a step forward toward improving assisted reproduction and developing new contraceptives.

Vondrakova J, Frolikova M, Ded L, Cerny J, Postlerova P, Palenikova V, Simonik O, Nahacka Z, Basus K, Valaskova E, Machan R, Pacey A, Holubcova Z, Koubek P, Ezrova Z, Park S, Liu R, Partha R, Clark N, Neuzil J, Ikawa M, Erickson K, Lam KS, Moore H, Komrskova K. MAIA, Fc receptor-like 3, supersedes JUNO as IZUMO1 receptor during human fertilization. Sci Adv. 2022 Sep 9;8(36):eabn0047. doi: 10.1126/sciadv.abn0047. Epub 2022 Sep 7. PMID: 36070373; PMCID: PMC9451160.

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