Abstract
In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.
Highlights
Foetal development, which represents a critical period, can have major ramifications on the proper growth and development of the foetus and on risk for disease later in life
Brain weight and body weight were decreased in the intrauterine growth restriction (IUGR) group
The dams were fed with a 10% low-protein diet during pregnancy, and we selected offspring according to IUGR standards
Summary
Foetal development, which represents a critical period, can have major ramifications on the proper growth and development of the foetus and on risk for disease later in life. MiRNAs are approximately 21–25-nucleotide long evolutionarily conserved non-coding RNAs that function as endogenous regulators of post-transcriptional gene expression. These small RNAs are capable of controlling gene expression by mediating mRNA degradation or translation inhibition[5]. Previous studies have demonstrated that miRNAs play important roles in IUGR. MiR-141 was significantly up-regulated in both the placental tissues and plasma of women whose babies experienced IUGR and plays an important role in the pathogenesis of IUGR by suppressing pleomorphic adenoma gene 18,9. The primary goal of our study was to identify the hippocampal expression profiles of miRNAs that differed significantly between rats with IUGR and normal rats. The target genes of the differentially expressed miRNAs were predicted using bioinformatics methods, and a global analysis of the biological pathways and genes regulated by these miRNAs was performed
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