Developmental Biology - Brain Development|
Fertilization Discovery May Lead to Male Contraceptive
New discovery could lead to a male contraceptive while also helping infertile couples...
An unexpected discovery from the University of Virginia (UVA) School of Medicine reveals new insight into how sperm and egg fuse. The findings could have major implications for couples battling infertility - and might lead to a male contraceptive.
The old notion of the egg as a passive partner to sperm entry is out. Instead, researchers found molecules on the surface of the egg that bind with a corresponding substance on sperm — facilitates fusion of the two.
"High school biology taught us a very sperm-centric version of fertilization. Now, it's clear this is a dynamic process where both sperm and egg are equally active and involved in achieving fertilization."
Kodi S. Ravichandran PhD;
The Center for Cell Clearance, School of Medicine;
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA; Department of Biomedical Molecular Biology, Ghent University, and the UGent-VIB Center for Inflammation Research, Technologiepark, Ghent, Belgium.
Not Dead Yet
A few years back, Kodi Ravichandran and Jeffrey Lysiak's laboratories started collaborating on how immature sperm move through their developmental stages in the testes. During which they noticed something unusual. Some immature sperm appeared to be dying — but instead were alive and healthy.
"These sperm had a molecular marker on their surface suggestive of a dying cell. Yet, this marker grew stronger as the sperm matured. Initially this made no sense. We had to do a lot of experiments to show indeed, these were live, motile sperm."
Jeffrey J. Lysiak PhD:
The Center for Cell Clearance, School of Medicine;
Department of Urology, School of Medicine,University of Virginia, Charlottesville, VA, USA.
The marker, phosphatidylserine (PS), is normally inside sperm cells until cell death is triggered. But, is deliberately exposed on the surface of healthy, live sperm.
Simultaneously, an egg expresses protein that partners specifically with PS on sperm. Egg recognition of PS, along with other interactions, promotes sperm-egg fusion.
However, masking PS on sperm, or preventing egg receptors from recognizing PS on sperm, blocks fertilization quite efficiently.
Doctors might be able to enhance the exposure of PS on sperm to promote and improve the chance of conception. Also, examination of sperm for the PS markers before in-vitro fertilization, could help prevent multiple fertilization attempts and help reduce costs to couples.
"Currently, semen analysis primarily looks at the number of sperm, if they can swim and how healthy they look," Lysiak explains. "It doesn't provide much of an idea of the sperm's fitness to fertilize." Ravichandran and Lysiak's groups have now designed a test to determine fertilization fitness of sperm based on the exposure of their PS.
Ravichandran and Lysiak believe finding a way to mask PS on sperm may be a potential form of contraception.
According to Ravichandran: "It is a very likely possibility. We blocked phosphatidylserine in three or four different ways [in petri dishes], and are pleasantly surprised how well it blocks sperm-egg fusion."
Ravichandran, chairman of UVA's Department of Microbiology, Immunology and Cancer Biology, and Lysiak, of the Department of Urology, plan to explore the basic-science related to fertilization through a company they have formed called PS-Fertility. Their research is published in the journal .
Fertilization is essential for species survival. Although Izumo1 and Juno are critical for initial interaction between gametes, additional molecules necessary for sperm:egg fusion on both the sperm and the oocyte remain to be defined. Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts. Collectively, these data identify phosphatidylserine on viable sperm and PtdSer recognition receptors on oocytes as key players in sperm:egg fusion.
Claudia M. Rival, Wenhao Xu, Laura S. Shankman, Sho Morioka, Sanja Arandjelovic, Chang Sup Lee, Karen M. Wheeler, Ryan P. Smith, Lisa B. Haney, Brant E. Isakson, Scott Purcell, Jeffrey J. Lysiak and Kodi S. Ravichandran.
The authors thank members of the Ravichandran laboratory for discussions and critical reading of manuscript; Virginia Rubianes and Sheri VanHoose (Histology Core, UVa) and Pat Pramoonjago (Biorepository and Tissue Research Facility, UVa). We also acknowledge the early discussions on this topic with Dr. John Herr that provided some of the inputs. This work is supported by grants to K.S.R. from the NIGMS (GM064709), the Center for Cell Signaling at the University of Virginia, and the Odysseus I award from the FWO (Belgium). Additional support was provided via the T32HL007284 and a fellowship from the American Cancer Society (L.S.S.). S.M. is supported by grants from the Mishima-Kaiun Memorial Foundation and The Kanae Foundation for the Promotion of Medical Science. This project has also received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 835243).
The authors declare no competing interests.
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Nov 19 2019 Fetal Timeline Maternal Timeline News
"Currently, semen analysis primarily looks at the number of sperm, if they can swim and how healthy they look. It doesn't provide much of an idea of the sperm's fitness to fertilize." Doctors might be able to enhance the exposure of PS
on sperm to promote and improve conception.
Jeffrey J. Lysiak PhD. CREDIT Public Domain.