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DEVELOPMENTAL BIOLOGY Death Protein May Cause Neural Tube Defects in Babies of Diabetic Mothers Study Adds Impetus for Blood Sugar Control in Diabetic and Obese Women Diabetic mothers could have a surprising culprit to blame for their high risk of having babies with neural tube defects. Scientists at Joslin Diabetes Center, working with mice, report in the March 15 Genes and Development that a protein normally involved in programmed cell death may, as a consequence of high blood sugar, mistakenly tell cells of the nascent neural tube to die. P53 tells neural tube cells to die. A Pax-3 mutant mouse embryo lacking p53 appears healthy (center) while one with p53 is defective (left). Arrows point to dead cells at the top and bottom of the neural tube. Courtesy of Mary Loeken It is not clear whether the protein, p53, plays a similar role in human neural tube defects, which include spina bifida and exencephaly. But the report provides a possible explanation for a class of birth 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 the disease. That risk could increase as diabetes and obesity, both of which can cause high blood sugar, make 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 being diabetic," said Mary Loeken, HMS assistant professor of medicine (physiology), "and yet their blood glucose may be higher than normal." Such women might be advised to lower their blood sugar levels in an attempt to avoid triggering the events that can result in the activation of p53. "Despite the availability of prepregnancy counseling, congenital defects are still high in the diabetic population," said Mary Loeken (right), shown with Lydie Pani. Photo by Steve Gilbert Patient Alert "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 her risk of being diabetic and whether she should be screened for diabetes." What makes the discovery surprising is that p53 has attained celebrity status for its role in preventing cancer but has rarely been implicated in birth defects. Many malignancies are due to a lack of functional p53, which allows cancer cells to escape normal cell death and proliferate. "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 dead cells along the unfused neural tube. It appeared that the cells had committed suicide. Protein Partners Blocking a Path Toward Cancer The discovery that p53, unrestrained by Pax-3, plays the villain--killing neural tube cells--reverses its good-guy role in cancer. Cells often turn cancerous because they lack sufficient p53 to signal them to undergo cell death. It turns out Pax-3 may play a role in such a scenario, at least in some cancers. According to Mary Loeken, expression of Pax-3 could put a brake on p53 activity in tumor cells. In fact, melanomas and other cancers have been associated with high levels of Pax-3. The discovery could lead to new methods of diagnosis and treatment of such cancers. For example, it might be possible to detect melanomas by the presence of elevated Pax-3. 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, a research fellow; Melissa Horal, a senior research assistant; and Loeken created mice lacking both the p53 and Pax-3 proteins. The mutant embryos appeared perfectly healthy, findings that suggest 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 apoptosis. The embryos had 50 percent fewer 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 the embryos of diabetic mothers to save their neural tubes from p53-dependent cell death." --Misia Landau