For two decades, scientists have known that the gene Pax3, which is required for closure of the neural tube during fetal development, is involved in neural tube defects such as spina bifida. What they hadn’t figured out was why that gene malfunctioned during diabetic pregnancies. Fortunately, that mystery has now been cleared up.
A team of researchers led by Mary Loeken, an HMS associate professor of medicine and an investigator in the Islet Cell and Regenerative Biology research section at Joslin Diabetes Center, has discovered a molecular pathway responsible for neural tube defects in diabetic pregnancies. Their findings appear in the October 2014 issue of Diabetes.
The neural tube is the body’s first step in assembling the spinal cord and the brain; it forms within the first two to four weeks of gestation. A developing embryo carried by a woman with diabetes runs a greater than average risk that its neural tube will fail to close. This failure can result in anencephaly, a fatal disorder, or spina bifida, which can lead to motor impairment and other disabilities.
In previous research, Loeken found that when Pax3 is exposed to high levels of glucose, it doesn’t turn on as often as it should. In this recent work, Loeken describes why. The key is Dnmt3b, a subtype of the enzyme DNA methyltransferase (Dnmt), which adds methyl groups to cytosine, one of the four bases that make up a DNA molecule.
In normal development, Dnmt adds methyl groups to the cytosines around the Pax3 gene and then tapers off its activity before the Pax3 gene turns on. But when Dnmt3b is exposed to high levels of glucose, it becomes overactive and causes Dnmt to keep adding methyl groups to the cytosines near the Pax3 gene. This prevents Pax3 from turning on—and the neural tube from closing.
Although it would appear that the way to prevent neural tube defects would be to stop Dnmt3b, Loeken cautions against such radical treatment. “This is a tightly regulated process, and Dmnt3b is essential for embryonic survival.”
A treatment that may come out of this research is better stem cell therapy. “We might be able to exploit these pathways to make more competent stem cells to repair the congenital malformations,” says Loeken.
Neural-tube defects occur in nondiabetic pregnancies as well, affecting about 1,500 births in this nation every year and about 300,000 worldwide. Until a treatment is developed, the best safeguard against complications in diabetic pregnancies, Loeken points out, is to rigidly control the blood glucose levels of women who hope to become pregnant, even before they do.
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