Neuronal let-7b-5p acts through the Hippo-YAP pathway in neonatal encephalopathy

Ponnusamy, Vennila, Ip, Richard T. H., Mohamed, Moumin A. E. K., Clarke, Paul, Wozniak, Eva, Mein, Charles, Schwendimann, Leslie, Barlas, Akif, Chisholm, Philippa, Chakkarapani, Ela, Michael-Titus, Adina T., Gressens, Pierre, Yip, Ping K. and Shah, Divyen K. (2021) Neuronal let-7b-5p acts through the Hippo-YAP pathway in neonatal encephalopathy. Communications Biology, 4. ISSN 2399-3642

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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.

Item Type: Article
Uncontrolled Keywords: medicine (miscellaneous),biochemistry, genetics and molecular biology(all),agricultural and biological sciences(all) ,/dk/atira/pure/subjectarea/asjc/2700/2701
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 07 Oct 2021 01:33
Last Modified: 27 Oct 2021 02:22
URI: https://ueaeprints.uea.ac.uk/id/eprint/81587
DOI: 10.1038/s42003-021-02672-3

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