Master molecule SRC-2 sets stage for embryo implantation
The penetration of sperm into an egg is critical for pregnancy, but the implantation of the developing blastocyst into the endometrium – the lining of the uterus – is an equally important step that requires the input of the master molecule steroid receptor coactivator-2 (SRC-2), said researchers from Baylor College of Medicine in a report that appears online in the open access journal PLoS Genetics.
“Understanding how SRC-2 reprograms the endometrium to be receptive to implantation is a critical to developing methods to help women at high risk for early pregnancy loss,” said Dr. Bert O’Malley, chair of molecular and cellular biology at BCM and a corresponding author of the report with Dr. John Lydon, associate professor of molecular and cellular biology at BCM.
The endometrium is the lining of the uterus. When the blastocyst or early embryo that results from the joining of egg and sperm enters the uterus, the lining or endometrium must be able to accept and encourage implantation. This begins the process of development of both the embryo and the placenta that feeds it.
In studies that used mice and human cell lines, O’Malley, Lydon and his colleagues showed that SRC-2 modulates the response of endometrial cells to the pregnancy hormone progesterone. In doing so, it increases energy production that is dependent on progesterone. This energy is required for the next round of cell division among a special endometrial cell population known as stromal cells, which are the product of embryonic stem cells. These stromal cells need to grow and increase in number to create a receptive environment for implantation of the egg.
“There is a tremendous amount of energy for this process,” said O’Malley. “This coactivator causes the creation of energy by emphasizing an energetic pathway called glycolysis, where sugar is converted into ATP (adenosine triphosphate known as the ‘energy of life’), lipids (fats) and factors that are required for cellular interactions.”
The finding is not only important for understanding how SRC-2 prepares the body for embryo implantation, but it also may explain how this important coactivator plays a role in other areas such as preterm labor and problems with the endometrium such as leiomyoma (a rare benign tumor sometimes found in the uterus) and polycystic ovary syndrome, a hormonal imbalance disorder that can affect the menstrual cycle, the ability to have children and other factors.
The finding may enable better treatment of women with frequent miscarriages who may have a uterus that is not receptive to implantation.
It also demonstrates the importance of SRC-2 and other steroid receptor coactivators such as SRC-1 (discovered by O’Malley) and SRC-3 that play important roles in the mechanics of life itself. SRC-1 is involved in inflammation and metabolism. SRC-2 controls the accumulation and use of energy or fats.
“What does fat have to do with reproduction?” said O’Malley. “If you don’t have a food source, you don’t reproduce. You won’t get pregnant.”
In animals, the process evolved as a protective mechanism to keep the mother alive. If the mother lacked enough stored fat and still got pregnant, she could not hunt to keep herself and the developing fetus alive. She and it would die, endangering the species.
“Now some of these things are adding to problems of obesity and diabetes in the population,” O’Malley said. “In the distant past, they saved lives and are still vital for hunting animals.”
SRC-3 coordinates the responses for growth, and it plays a role in cancer as well.
Modulating the responses of these steroid receptor coactivators might play an important role in addressing diseases such as diabetes, obesity and cancer.
“Finding out how something works and the big picture ramifications in terms of its physiology and its relationship to disease is important,” said O’Malley. “The final thing is to come up with a drug to affect it, depending on its role in a particular to disease. We know we can find drugs to regulate these coactivators.”
Others who took part in this work include the lead author Ramakrishna Kommagani, and Maria M. Szwarc, Ertug Kovanci, William E. Gibbons, Nagireddy Putluri, Suman Maity, Chad J. Creighton, Arun Sreekumar and Francesco J. DeMayo, all of BCM.
Funding for this work came from the National Institute of Child Health and Human Development.
O’Malley also holds the Thomas C. Thompson Chair in Cell Biology.