Abstract
Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated. Herein, we identify let-7b-5p as a significant microRNA in neonates with moderate to severe encephalopathy from dried blood spots using next generation sequencing. Validation studies using Reverse Transcription and quantitative Polymerase Chain Reaction on 45 neonates showed that let-7b-5p expression was increased on day 1 in neonates with moderate to severe encephalopathy with unfavourable outcome when compared to those with mild encephalopathy. Mechanistic studies performed on glucose deprived cell cultures and the cerebral cortex of two animal models of perinatal brain injury, namely hypoxic-ischaemic and intrauterine inflammation models confirm that let-7b-5p is associated with the apoptotic Hippo pathway. Significant reduction in neuronal let-7b-5p expression corresponded with activated Hippo pathway, with increased neuronal/nuclear ratio of Yes Associated Protein (YAP) and increased neuronal cleaved caspase-3 expression in both animal models. Similar results were noted for let-7b-5p and YAP expression in glucose-deprived cell cultures. Reduced nuclear YAP with decreased intracellular let-7b-5p correlated with neuronal apoptosis in conditions of metabolic stress. This finding of the Hippo-YAP association with let-7b needs validation in larger cohorts to further our knowledge on let-7b-5p as a biomarker for neonatal encephalopathy.
Highlights
Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated
A number of miRNAs were differentially expressed between the groups with unadjusted p value < 0.05 (Fig. 1b) and the heatmap generated after correcting for false discovery rate (FDR) < 0.05 revealed 17 significant miRNAs (Fig. 1c) which were differentially expressed in healthy cord blood compared to that of neonatal blood samples
For the first time, we report the association of let-7b-5p with the apoptotic Hippo pathway in the context of Neonatal encephalopathy (NE), following validation of let-7b-5p in an independent cohort of neonates with NE
Summary
Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated. The Hippo signalling pathway is an important, well-conserved pathway known to function across a number of mammalian species[12,13] with a role in regulating apoptosis and cell proliferation Within this pathway, there are kinase complexes that negatively regulate the activities of the mammalian Yorkie (YKi) homologue named Yes Associated Protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). We show using both in vitro and in vivo models of NE that neuronal apoptosis is associated with a decrease in let-7b-5p and a reduced nuclear location of YAP This indicates a potential role of the Hippo pathway in the cell death associated with NE
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