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Am J Physiol Regul Integr Comp Physiol 288: R1038-R1045, 2005. First published November 24, 2004; doi:10.1152/ajpregu.00701.2004
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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Nonresponsiveness of cerebral p53-MDM2 functional circuit in newborn rat pups rendered IUGR via uteroplacental insufficiency

Xingrao Ke, Robert A. McKnight, Zheng-ming Wang, Xing Yu, Laiyi Wang, Christopher W. Callaway, Kurt H. Albertine, and Robert H. Lane

Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah

Submitted 13 October 2004 ; accepted in final form 19 November 2004

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 affect cerebral gene expression of Bcl-2 and predispose the newborn IUGR rat toward cerebral apoptosis when challenged with perinatal hypoxia. Expression of Bcl-2, as well as the proapoptotic 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 toward cerebral apoptosis suggests that the p53-MDM2 "functional" circuit may be perturbed in the newborn IUGR 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 (Ser15) protein levels in the brain at term. Increased expression of phospho-p53 (Ser15) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-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 (Ser166) protein levels in the IUGR rat pups. We conclude that the cerebral MDM2 response to increased p53 expression is not present in the newborn IUGR rat pup, and we speculate that this contributes to the predisposition of the IUGR fetus toward perinatal and long-term neurodevelopmental morbidities.

apoptosis; hippocampus; white matter; amygdala; intrauterine growth retardation


Address for reprint requests and other correspondence: R. H. Lane, Div. of Neonatology, Dept. of Pediatrics, Univ. of Utah School of Medicine, 30 North 1900 East, Rm. 2A100, Salt Lake City, UT 84132-2202 (E-mail: robert.lane{at}hsc.utah.edu)




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