Abstract
Neural tube defects (NTDs) are the most severe congenital malformations that result from failure of neural tube closure during early embryonic development, and the underlying molecular mechanisms remain elusive. Mitophagy is the best-known way of mitochondrial quality control. However, the role and regulation of mitophagy in NTDs have not yet been elucidated. In this study, we used an all-trans retinoic acid (ATRA)-induced rat model to investigate mitophagy and its underlying mechanism in spina bifida aperta (SBA). The results of western blot, immunofluorescence and RT-qPCR analyses indicated that mitophagy was impaired and Sirt1 was downregulated in SBA. Administration of resveratrol-a strong specific Sirt1 activator-activated Sirt1, thus attenuating autophagy suppression and ameliorating SBA. RNA-sequencing and bioinformatics analysis results indicated that transcriptional regulation played an important role in NTDs. A luciferase reporter assay was performed to demonstrate that the transcription factor Bhlhe40 directly bound to and negatively regulated Sirt1 expression. Further, we discovered that the Bhlhe40/Sirt1 axis regulated mitophagy in neural stem cells. Collectively, our results for the first time demonstrate that Bhlhe40/Sirt1 axis regulated mitophagy is implicated in ATRA-induced SBA. Our findings provide new insights into pathogenesis of NTDs and a basis for potential therapeutic targets for NTDs.
Highlights
Neural tube defects (NTDs), such as anencephaly and spina bifida, represent the most severe and common congenital malformations of the central nervous system resulting in infant deaths and severe disabilities, bring undue burden to the ill infant and their families as well as society (Greene and Copp, 2014)
We demonstrated for the first time that the Bhlhe40/silent information regulator factor 2-related enzyme 1 (Sirt1) axis regulates mitophagy function in vitro
Emerging evidence suggests that mitochondria are critical regulatory organelles in determining neural stem cell fate, both in initial neural development and in adult neurogenesis (Khacho et al, 2019)
Summary
Neural tube defects (NTDs), such as anencephaly and spina bifida, represent the most severe and common congenital malformations of the central nervous system resulting in infant deaths and severe disabilities, bring undue burden to the ill infant and their families as well as society (Greene and Copp, 2014). NTDs have a complex etiology and mainly result from incomplete closure. Mitophagy in Spina Bifida Aperta of the neural tube during early embryonic development. Current treatment strategies for NTDs are not satisfactory because the pathogenesis is insufficiently understood (Norkett et al, 2016; Radic et al, 2019). In-depth study of the mechanisms underlying NTD pathogenesis and the development of scientific prevention and treatment methods are of great significance for reducing the malformation and disability rates, improving patient quality of life and reducing societal burden
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