Nuclear factor I-C disrupts cellular homeostasis between autophagy and apoptosis via miR-200b-Ambra1 in neural tube defects

• DOI: 10.1038/s41419-021-04473-2
• Publication Date: 2021-12-20T13:07:55Z
• Authors: Wanqi Huang; Tianchu Huang; Yusi Liu; Jialin Fu; Xiaowei Wei; Dan Liu; Wei Ma; Hui Gu; Zhengwei Yuan
• Keywords: Male; 0301 basic medicine; Embryonic Development; Apoptosis; Transfection; Article; Mice; 03 medical and health sciences; Neural Stem Cells; Pregnancy; Autophagy; Animals; Homeostasis; Neural Tube Defects; Adaptor Proteins, Signal Transducing; Cell Line, Transformed; QH573-671; Mice, Inbred C57BL; Disease Models, Animal; MicroRNAs; NFI Transcription Factors; Gene Knockdown Techniques; Female; Cytology; Signal Transduction

AbstractImpaired 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.