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1 Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: robert.lane{at}hsc.utah.edu.
Severe uteroplacental insufficiency causes cerebral apoptosis in the fetus. Moderate uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and increases the risk of postnatal neurological morbidity. In the rat, uteroplacental insufficiency and IUGR affects cerebral gene expression of Bcl-2 and predisposes the IUGR newborn rat towards cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the pro-apoptotic protein Bax, is regulated by p53. p53 also induces MDM2 transcription, which functions to limit further p53-induced apoptosis. The predisposition of the IUGR fetus towards cerebral apoptosis suggests that the p53-MDM2 functional circuit may be perturbed in the IUGR newborn rat brain. We hypothesized that MDM2 cerebral expression does not increase in response to increased p53 expression or increased levels of phospho-p53 (Ser15), an activated form of p53. To prove this hypothesis, we induced IUGR through bilateral uterine ligation of the pregnant rat. Uteroplacental insufficiency significantly increased p53 mRNA, total p53 protein, and phospho-p53 (Ser 15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and TUNEL positive cells were localized to the CA1 region of the hippocampus, the subcortical and periventricular white matter, and the amygdala of the IUGR rat brain. In contrast, uteroplacental insufficiency decreased cerebral MDM2 mRNA and phospho-MDM2 Ser (166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the IUGR newborn rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus towards perinatal and long term neurodevelopmental morbidities.
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