Of Mice and Women
Mice lacking a molecule usually found on the surface of cells in the womb have fertility problems, according to a study by US researchers.
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| | Jerold Chun |
Jerold Chun and Xiaoqin Ye at The Scripps Research Institute and colleagues at The University of Tokyo, Washington State University, and the Fred Hutchinson Cancer Research Center demonstrated that mice lacking the receptor for lysophosphatidic acid (LPA3) produce eggs normally, that can be fertilized, but the resulting healthy embryos fail to implant normally in the womb. "This is a receptor that wasn't on anyone's radar screen from a fertility standpoint," says Chun, "our results offer new insights on lipid signals and fertility." This finding could be important in understanding human fertility problems as women also express LPA receptors in their wombs. It could open up a new area of fertility research.
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| Embryo implantation fails without the LPA receptor |
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If follow up research shows that these receptors are relevant to embryo implantation in humans, then the mechanisms involving these proteins might make good targets for therapeutic intervention. This might lead ultimately to new treatments for the millions of women affected by infertility.
Despite recent advances in understanding fertility problems, The American Society for Reproductive Medicine estimates that the cause of infertility remains a mystery in about a fifth of cases. Implantation of the embryo in the womb may underlie many such cases. The molecular pathway revealed by Chun and his colleagues in the laboratory suggests one possible explanation. "Other possibilities include genetic defects in the embryo itself, or autoimmune processes against maternal or embryonic tissues," Chun told Reactive Reports.
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| Lysophospholipid receptors and down-stream signaling pathways |
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Chun and his colleagues identified the first lysophospholipid receptor about ten years ago, when he was at the University of California, San Diego, and since then eight more of these receptors have been identified. The LPA receptors are all proteins of the type known as a G protein-coupled receptor (GPCR). This is a common type of receptor molecule in the body, and an important class of targets for the design of drugs. Indeed, about half of the medicines on the market target such GPCRs. Chun and his team were hoping to make further inroads into understanding of LPA receptors and created mice that lacked LPA3 receptors and observed that they suffered from fertility problems.
They analyzed the timing and spacing of embryos in the womb and found that it was different to that seen for mice with the receptor. Moreover, the number of implanted embryos was reduced and several embryos were clustered abnormally sharing a single placenta. "Here is a clear effect on the ability of embryos to implant and position normally," says Chun. "It identifies a new molecular influence - a lipid molecule - on this whole process."
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"The identification of this lipid-receptor pathway implicates a theoretical 'parade' of interacting molecules that precede or follow from the LPA3 receptor, so called 'up-stream' and 'down-stream' factors," Chun told Reactive Reports. He adds that, "These factors may now be assessed as potential diagnostic and therapeutic targets for understanding fertility and infertility. Improving the actions of the receptor might increase fertility." In contrast, defects in receptor function produced by autoimmune or genetic diseases that interfere with LPA3 function might account for some infertility cases. Chun told us.
Nature, 2005, in press; http://dx.doi.org/10.1038/nature03505
http://www.scripps.edu/mb/chun/
http://www.4woman.gov/faq/infertility.htm
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