Researchers Suggest Cause for Neural Tube Defects in Babies of Mothers with Diabetes
BOSTON — March 14, 2002 — Diabetic mothers could have a surprising culprit to blame for their higher risk of having babies with neural tube defects. Scientists at Joslin Diabetes Center working with mice report in the March 15 issue of Genes and Development that a protein normally involved in programmed cell death may, as a consequence of high blood sugar levels, mistakenly tell the cells of the early developing neural tube to die.
It is not clear whether the protein, p53, plays a similar role in human neural tube defects, which include spina bifida (where the spinal cord is not completely enclosed) and exencephaly (where the brain is exposed and the skull is not fully formed). But the report provides a possible explanation for a class of defects that appears to be on the rise. Even with good control of diabetes, the risk for neural tube and other birth defects is two to five times higher than normal if a mother has diabetes. That risk could increase as diabetes and obesity, both of which can cause high blood sugar, makes inroads into younger populations.
"I think there is a very large population of women at risk for having a baby with a neural tube defect who are not being looked at aggressively because they have not been diagnosed as having diabetes, and yet, their blood glucose may be higher than normal" said Mary Loeken, Ph.D., who is a researcher at Joslin and assistant professor of medicine (physiology) at Harvard Medical School. Such women might be advised to lower their blood sugar levels in an attempt to avoid triggering the set of events that can result in the activating of p53.
"The best we can do right now is to try to prevent the elevated glucose levels that happen during diabetes," said Loeken. "A woman who is overweight and considering becoming pregnant should discuss with her doctor what her risk is for developing diabetes and whether she should be screened for diabetes."
What makes the discovery surprising is that p53 has attained celebrity status for its role in cancer but has rarely been implicated in birth defects. Many malignancies are due to a lack of functional p53 which, in turn, allows cancer cells to escape normal cell death and keep proliferating. "Few people have studied the role of p53 in embryonic development," said Loeken.
She first suspected p53 might be involved in neural tube defects while investigating the role of another protein, Pax-3. Mice lacking two functional Pax-3 genes are always born with neural tube defects. In addition, embryos of diabetic mouse mothers develop neural tube defects three times more often than do those of normal mice, and they have low levels of Pax-3 gene expression. While examining these embryos, she and her colleagues noticed that all of the cells at the site of the defect were dead.
She suspected that the lack of Pax-3 might somehow be providing an opportunity for p53 to exert its cell-death inducing effects. To test this hypothesis, Lydie Pani, research fellow, Melissa Horal, senior research assistant, and Loeken created mice lacking both the p53 and Pax-3 proteins. The mutant embryos appeared perfectly healthy. "The embryos had absolutely no neural tube defects when otherwise they all would have had neural tube defects," Loeken said. The findings suggest that Pax-3's normal role is to keep p53 in check.
To confirm p53's role, Loeken and colleagues gave mice lacking Pax-3 genes a drug that inhibits p53-dependent programmed cell death. The p53 inhibiting drug prevented about 50 percent of the defects. Additional experiments suggest that Pax-3 may keep p53 in check by interfering with the stability of the p53 protein.
Although it is not clear what role Pax-3 plays in human neural tube defects, the PAX-3 gene is present in humans. "If it does the same thing as in mice, then human neural tube defects associated with diabetes may be due to the release of p53-dependent cell death," said Loeken. "What we would want to do therapeutically is prevent the inhibition of PAX-3 expression in embryos of diabetic mothers, to save their neural tubes from p53-dependent cell death."
The cells that become melanoma, an aggressive type of skin cancer, also embryonically express PAX-3. Other researchers have recently demonstrated that many human melanoma tumors express PAX-3. "Perhaps these cells have returned to an embryonic behavior and re-emerged PAX-3 expression inhibits p53 dependent cell death, enabling the tumors to grow unimpeded," says Loeken.
