IUGR disrupts the PPAR gamma-Setd8-H4K20me(1) and Wnt signaling pathways in the juvenile rat hippocampus

摘要

Intrauterine growth restriction (IUGR) programs neurodevelopmental impairment and long-term neurological morbidities. Neurological morbidities in IUGR infants are correlated with changes hippocampal volume. We previously demonstrated that IUGR alters hippocampal cellular composition in both neonatal and juvenile rat pups in association with altered hippocampal gene expression and epigenetic determinants. PPAR gamma signaling is important for neurodevelopment as well as epigenetic integrity in the brain via the PPAR gamma-Setd8-H4K20me(1) axis and Wnt signaling. We hypothesized that IUGR would decrease expression of PPAR gamma, Setd8, and H4K20me(1) in juvenile rat hippocampus. We further hypothesized that reduced PPAR gamma-Setd8-H4K20me(1) would be associated with reduced Wnt signaling genes Wnt3a and beta-catenin, and wnt target gene Axin2. To test our hypothesis we used a rat model of uteroplacental insufficiency-induced IUGR. We demonstrated that PPAR gamma localizes to oligodendrocytes, neurons and astrocytes within the juvenile rat hippocampus. We also demonstrated that IUGR reduces levels of PPAR gamma, Setd8 and H4K20me(1) in male and female juvenile rat hippocampus in conjunction with reduced Wnt signaling components in only male rats. We speculate that reduced PPAR gamma and Wnt signaling may contribute to altered hippocampal cellular composition which, in turn, may contribute to impaired neurodevelopment and subsequent neurocognitive impairment in IUGR offspring. (C) 2014 ISDN. Published by Elsevier Ltd. All rights reserved.