Scientists Identify Infertility Molecule

By Jason Socrates Bardi

Scientists at The Scripps Research Institute are reporting that mice created to lack a certain type of molecule known as an LPA receptor have fertility problems, which suggests that these receptors play a major role in conception.

In the latest issue of the journal Nature, the scientists detail how mice that lack LPA receptors, which normally appear on the surface of cells in a mouse's womb, have fertility problems. These mice are able to produce eggs normally, so that the eggs can be fertilized, but the resulting embryos, which are otherwise healthy, have problems implanting in the womb—the last step in conception.

This is significant because women also have these LPA receptors expressed in their wombs. The discovery that the LPA receptors affect fertility in mice may open a new area of fertility research and treatment for humans.

"This is a receptor that wasn't on anyone's radar screen from a fertility standpoint," says Professor Jerold Chun, who conducted the study with Research Associate Xiaoqin Ye and their colleagues at The University of Tokyo, Washington State University, and the Fred Hutchinson Cancer Research Center. "[These results] offer new insights on lipid signals and fertility."

If the receptors do turn out to be relevant to embryo implantation in humans, then the mechanisms involving these proteins might make good targets for therapeutic intervention, perhaps even leading to new treatments and successful pregnancies for some of the more than 6 million American women affected by infertility.

Fertility and the Demographics of the Western World

In the Western world, the last few decades have seen a dramatic shift in when women are choosing to have their first children. According to the U.S. Centers for Disease Control and Prevention, the average age of first-time mothers increased from about 21.4 in 1970 to nearly 25 in 2000.

Many women wait until they are well into their thirties or later before having their first child. In fact, the CDC reports that in 2002, the latest year for which the statistics are available, more than 100,000 women over the age of 40 gave birth. This was the first time that this number topped 100,000 in a given year.

The success of these older-than-traditional women at childbearing belies the difficulty that many women over the age of thirty have in getting pregnant.

Successful conception depends on a variety of factors. A man has to produce an adequate amount of healthy sperm, and a woman has to produce healthy eggs. The sperm has to be able to travel up the fallopian tubes to reach the egg, and once there, it must be able to fertilize the egg. Finally, the fertilized egg must become a viable embryo and implant in the uterus.

Problems can occur in any one of these steps along the way and cause infertility. A man might not produce enough sperm, or his sperm might be unable to reach the eggs. A woman might have problems producing eggs or her fallopian tubes may be blocked.

Infertility becomes more pronounced for mature women who are attempting pregnancy because a woman's egg production decreases with age, especially after the age of 35.

Often, women will undergo treatments for infertility that range from taking hormones to stimulate ovulation to having their eggs harvested by doctors, fertilized by their partner's sperm outside their bodies, and finally having the early embryos implanted directly into their wombs (the technique of in vitro fertilization).

Despite the existence of these therapies, however, the molecular mechanisms that govern female infertility are not completely understood. In fact, the cause of infertility is not always easy to diagnose. The American Society for Reproductive Medicine estimates that the cause of infertility remains a mystery in about 20 percent of all cases.

One issue may be that once a woman's egg is fertilized and made into an embryo, it must descend to the womb and implant there, where it will grow into a fetus. But the factors that control whether an embryo is able to implant successfully inside a womb have not been known.

Now Chun and his colleagues have discovered a new molecular pathway that influences fertility, at least in mice—and one that directly affects the ability of mouse embryos to implant in their mother's womb.

LPA Receptors and Implantation

The pathway that affects implantation involves a particular type of receptor molecule—a protein called a lysophosphatidic acid (LPA) receptor that can be found on the surfaces of cells in the brains and in the uteruses of mammals, where it binds to LPA, one type of phospholipid.

Phospholipids, molecules of fat with a charged head on one end, are commonly found in biological organisms and are generally regarded as essential structural components of cells. For instance, bilayers of phospholipids are the primary component of cellular membranes, those essential barriers that define the boundaries of cells and keep the molecules inside a cell separated from those outside a cell.

But many phospholipids are more than just simple structural elements. Some play significant signaling roles in the cell. LPA belongs to a family of phospholipids known as "lysophospholipids."  These molecules play a more active role in the mammalian body, acting as signals for many different developmental events and adult physiology.

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.

In the last few years, Chun and his colleagues have been pursuing basic research on LPA and its receptors to try to understand their roles, particularly in the brain—looking, for instance, at the effect of LPA on mammalian brain development. Recently, they showed that LPA can induce neurogenesis—the formation of new neurons—in mice, and can also participate in neuropathic pain models.

Wanting to go further, they created what is known as a knock-out mouse model for a specific LPA receptor. These are special mice that lack one or more particular genes of interest—in this case, a gene that encodes a particular LPA receptor called LPA3. With such a model, scientists can determine some of the overall physiological effects of an LPA receptor protein.

Creation of LPA receptor knock-out mice for LPA3 produced a surprising phenotype—fertility problems. Analyses revealed that the spacing of the embryos in the womb was altered, and the number of implanted embryos was reduced (mice have litters of pups, typically giving birth to eight or so offspring with each pregnancy). Also, instead of the normal types of implantation, the embryos were clustered and many of them ended up sharing a 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 small fat molecule—on this whole process."

Chun, Ye, and their colleagues went on to show that losing LPA receptors affected prostaglandin levels. Prostaglandin is a fatty acid found in mammals that is essential for normal implantation. Manipulating parts of LPA signaling may thus be a way of changing prostaglandin levels.

This is a significant finding because low implantation rates are one of the major issues facing women who use assisted reproductive technologies, and nobody has ever considered LPA signaling to be involved in implantation. If the same pathway turns out to be relevant in human embryo implantation, then there might be a way to stimulate LPA signaling with a drug that would increase the odds of implantation for women undergoing assisted reproduction.

The article, "LPA3-mediated lysophosphatidic acid signaling in embryo implantation and spacing" by Xiaoqin Ye, Kotaro Hama, James J. A. Contos, Brigitte Anliker, Asuka Inoue, Michael K. Skinner, Hiroshi Suzuki, Tomokazu Amano, Grace Kennedy, Hiroyuki Arai, Junken Aoki & Jerold Chun will appear in the May 5, 2005 issue of the journal Nature and after that date can be accessed at: http://dx.doi.org/10.1038/nature03505.

This work was supported by grants from the National Institute of Health/National Institute of Mental Health, the Swiss National Science Foundation, and the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) and grants-in-aid from the Ministry of Education, Science, Culture and Sports for the 21st Century Center of Excellence Program, Japan.

For more general information on infertility, see: http://www.4woman.gov/faq/infertility.htm

Send comments to: jasonb@scripps.edu