BOSTON, MA – December 28, 2011 - In a study published today in PLoS ONE, a team from Joslin Diabetes Center, headed by Mary R. Loeken, Ph. D., made a significant advance toward understanding the molecular mechanisms behind the elevated risk of birth defects among babies born to mothers with diabetes. They uncovered the mechanism by which Pax3, a protein whose production is reduced in embryos of diabetic mothers, functions and stops the activity of the cell-death protein p53.

Previous studies published by Loeken's lab showed that maternal hyperglycemia (high blood sugar) causes oxidative stress in the embryo, and inhibits expression of the Pax3 gene. The Pax3 protein, which is encoded by the Pax3 gene, regulates neural tube closure and cardiac neural crest development by blocking the activity of p53, which is a cell-death protein. Failure to block the activity of p53 leads to neural tube defects, such as spina bifida, and some defects of the major blood vessels associated with the heart.

In this study, Loeken’s team has discovered how the Pax3 protein interacts with p53 and disables the cell-death function of the protein in early-stage embryos of expectant mothers. 

Using mouse embryonic stem cells, they saw that the process involved three players—Pax3, p53, Mdm2 (Mdm2 being a protein that was already known to play a role in shutting down p53.)

It was previously thought that Pax3 was required for formation of certain structures in the early embryo, such as the neural tube, because it attaches to DNA and turns genes “on” or “off.”

This was thought to be the case because there were mutant Pax3 proteins in mice and humans that had defects in the parts of the protein that bind to DNA, and so, would not be able to properly turn genes “on” or “off.” Mouse embryos expressing these mutant Pax3 proteins develop neural tube defects and abnormal heart-associated blood vessels. 

But this study showed an unexpected physical interaction between Pax3, p53, and Mdm2 that did not involve attaching to DNA or switching genes “on” or “off.”

According to Loeken, “What we showed is that Pax3 stimulates the activity of Mdm2 to tag p53 for degradation. Interestingly, this process involves the structures of the Pax3 protein that bind to DNA, but this process does not involve DNA binding or regulation of gene expression.”

They saw that the parts of the Pax3 protein that normally attach to DNA instead attached to p53 and Mdm2. This stimulates Mdm2 to modify p53 so that it is broken down, which shuts down p53’s cell-death activity.

When expression of the Pax3 gene is reduced, however, it leads to insufficient amounts of Pax3 protein. This, in turn, prevents Mdm2 from tagging p53 to be degraded. p53 stays active, and this causes cells forming the embryo’s neural tube to die. 

Currently, the only way to prevent the suppression of Pax3 is to maintain tight control over glucose levels during the early stages of pregnancy. 

While this study did not lead to new drugs to prevent the suppression of Pax3 or the activation of p53, “it gives us a better understanding at the molecular level of why [certain] defects occur,” said Dr. Loeken. And more knowledge could eventually lead to more treatment options.

This study was funded by a grant from the National Institutes of Health.

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