Abstract
Impaired autophagy and excessive apoptosis disrupt cellular homeostasis and contribute to neural tube defects (NTDs), which are a group of fatal and disabling birth defects caused by the failure of neural tube closure during early embryonic development. However, the regulatory mechanisms underlying NTDs and outcomes remain elusive. Here, we report the role of the transcription factor nuclear factor I-C (NFIC) in maintaining cellular homeostasis in NTDs. We demonstrated that abnormally elevated levels of NFIC in a mouse model of NTDs can interact with the miR-200b promoter, leading to the activation of the transcription of miR-200b, which plays a critical role in NTD formation, as reported in our previous study. Furthermore, miR-200b represses autophagy and triggers apoptosis by directly targeting the autophagy-related gene Ambra1 (Autophagy/Beclin1 regulator 1). Notably, miR-200b inhibitors mitigate the unexpected effects of NFIC on autophagy and apoptosis. Collectively, these results indicate that the NFIC-miR-200b-Ambra1 axis, which integrates transcription- and epigenome-regulated miRNAs and an autophagy regulator, disrupts cellular homeostasis during the closure of the neural tube, and may provide new insight into NTD pathogenesis.
Highlights
Neural tube defects (NTDs) are a group of severe congenital malformations of the central nervous system, typified by spina bifida, anencephaly, and encephalocele, which are caused by incomplete closure of the neural tube during embryonic development [1, 2]
In a recent study, we determined that mitophagy in the spinal cord is inhibited in all-trans retinoic acid (ATRA)-induced spina bifida and that resveratrol treatment can reduce spina bifida formation by ameliorating mitophagy impairment; these findings indicate that autophagy is causally implicated in NTDs [13]
Our results revealed that the nuclear factor I-C (NFIC)-miR-200b pathway silences Ambra1, thereby disrupting cellular homeostasis via impaired autophagy and excessive apoptosis, and resulting in the failure
Summary
Neural tube defects (NTDs) are a group of severe congenital malformations of the central nervous system, typified by spina bifida, anencephaly, and encephalocele, which are caused by incomplete closure of the neural tube during embryonic development [1, 2]. The results showed that overexpression of NFIC resulted in remarkably increased luciferase activity in cells cotransfected with the miR-200b promoter (Fig. 2H).
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