Izumo, Meet Juno: fertilization receptors revealed

April 19, 2014Carole 6 Comments »

Unexplained infertility is the diagnosis that women (and men) get when everything looks normal but they can’t conceive. A recent study published in Nature this month may go a long way to explaining some of this unexplained infertility. Dr. Gavin Wright and his team at the Welcome Trust Sanger Institute in Britain have identified a molecular receptor on the surface of the egg which interacts with receptors on the sperm to start the cascade of molecular events that fertilize an egg.

We have long known that these receptors must exist on human sperm and egg — receptors had already been identified in other species. In 2005, Japanese researchers identified a mammalian receptor, named Izumo,  on mouse sperm cells. The molecule that binds Izumo was still a mystery until the publication of the article titled. “Juno is the egg Izumo receptor and is essential for mammalian fertilization”, Nature. 2014 Apr 16. doi: 10.1038/nature13203. [Epub ahead of print]

How they found the protein is pretty cool. They found Juno by using Izumo as bait; creating a artificial version of Izumo and seeing what molecules it hooked up with from the egg surface. The Juno receptor is also known as folate receptor 4 (Folr4) which has other uses in other cell types but was not known to be involved in fertilization until it was found to tango with Izumo.

The researchers took the experiment a step further by showing that if you knock out the Juno gene in mice so they don’t make the protein, these female mice are infertile. Eggs that lack Juno on their surface do not fuse with sperm. In the IVF lab, we have seen patients in which sperm surround the egg, but are swimming around and around, like ships looking for a port without luck. Absence of the Juno egg receptor would explain this phenomenon.

When we saw eggs with a flotilla of swimming non-binding sperm the morning after we added sperm to egg in the culture dish, we invariably had no fertilization.  But because there was no evidence that sperm had entered the egg, they were great candidates for secondary sperm injection. We had decent results if we did the ICSI as soon as possible the next morning when it was obvious that regular IVF had failed. With ICSI, because you inject the sperm directly into the egg, you don’t need any receptors to mediate fertilization.

Researchers are investigating whether the Juno protein is found to be absent in some infertile women and present in fertile women. If Juno is found to be predictive of  fertility, diagnostic tests to determine in advance whether a patient’s eggs have the Juno protein can’t be far behind. This test could guide treatment so that women without egg receptors would be offered ICSI right away, not after one or more failed regular IVF cycles.

Juno is present on the egg for fertilization but then is immediately shed from the surface of the egg –suggesting an explanation for how the egg prevents polyspermy- an abnormal condition where multiple sperm enter a single egg.  The block to polyspermy may well be accomplished by the egg dumping all the Juno molecules once “mission accomplished” by the first sperm.

This finding is significant on several levels. Understanding the molecular basis of fertilization may well lead to new fertility treatments or alternatively, new contraceptives. It really is a remarkable discovery. See a short video showing sperm-egg interactions and the scientists discussing their research here.

 

© 2014, Carole. All rights reserved.

6 Responses to this entry

  • It Is What It Is Says:

    This is very interesting and remarkable and if it leads to a test in women of its presence/absence could really improve things for women lacking.

    Can’t wait til we get to this point with transferred embryos and the dance between the embryo and the lining and why genetically normal embryos fail to implant.

  • Carole Says:

    I agree! My post-doctoral work was in embryo implantation so this is a long standing interest of mine. Unfortunately – relatively little progress over the last 20 years.

  • Amy Says:

    Hi, Carole. Wow, what a wonderful blog!! I have a question for you about Day-5 vs. Day-6 CCS-normal blasts. We have five CCS normal blasts. All of them received the same quality grade. (Sorry, I do not have the specific grade, but it’s the highest our clinic – which has some of the highest success rates in the country – gives.) (We used an egg donor.) Three of the blasts are day-5 and all of those blasts are female. Two of them are Day-6. One of the Day-6 blasts is female and one is male.

    We would love to have both a boy and a girl. But just as strongly, I’d like for this pregnancy to be twins.

    Our clinic says that while they normally transfer Day-5 embryos first, they do not track whether there’s a difference in success rates between Day-5 and Day-6 CCS normal embryos and we should just do whatever gender mix we’d most like without worrying that the Day-6 boy will be less likely to be viable. Based on some of what I’m reading here though – as well as what little research I could find – it sounds as though Day-6 embryos, in general, may not do as well as Day-5 embryos. I can’t really find anything about Day-5 vs. Day-6 CCS NORMAL embryos though. Could Day-5 embryos do somewhat better simply because more Day-5 embryos tend to be chromosomally normal? Or could it also be because Day 5 is the optimal time to transfer?

    Finally, thank you so much for your blog. What an incredible resource! And thanks, too, for all the compassion you show to the people writing you.

  • Carole Says:

    HI Amy,
    The quick answer to your first question is yes. Most of the literature on day 5 and day 6 that showed differences was not looking at embryos in which the aneuploidy state was known. It is possible, if not probable, that the lower pregnancy rate on day 6 had to do with aneuploid embryos maybe needing an additional day to get to blast stage-so you tended to seem more aneuploid embryos on day 6. However, if you test for embryos and remove those aneuploid embryos from the transfer group, my guess would be that differences between day 5 and 6 may very well disappear. So bottom line, you are transferring all euploid (normal) embryos, so day 5 vs day 6 probably makes little if any difference. The only way that day 5 would be optimal for transfer is that the implantation window may be slightly better but I think there is more wiggle room on that end because lots of programs report as many day 5 as day 6 pregnancies so I think the implantation effect may be less important than the aneuploid embryo effect. I would caution you against twins. The evidence is overwhelming that just because we can manage twins doesn’t mean it is a good or ideal pregnancy. Do yourself and your baby a favor by seriously considering the option of transferring one euploid embryo at a time. Good Luck!! Carole

  • Amy Says:

    Carole, thanks so much for the reply! Much much appreciated.

  • Jai Says:

    Fascinating post. Exactly what I was wondering about. But how come there is no discussion of whether the Izumo protein is being properly expressed in the sperm? Wouldn’t that be genetically controlled as well, and just as likely to show problems?

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