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.

The two monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), namely evolocumab and alirocumab, were first approved by the U.S. Food and Drug Administration (FDA) in 2015. PCSK9 inhibitor (PCSK9i) has served as a viable new therapeutic option to lower cholesterol levels and associated cardiovascular events. However, a better understanding of safety issue of PCSK9i is necessarily needed. We present here an increased risk of adverse pregnancy outcomes, including stillbirths and embryonic defects, particularly neural tube defects, following PCSK9i treatment harnessing a high-fat diet-based mouse model. Proteomics of PCSK9i-treated neural stem cells uncovered that PCSK9i may disrupt mitochondrial function via succinic dehydrogenase complex subunit A (SDHA), which is a key enzyme in the mitochondrial respiratory chain. Furthermore, PCSK9i-induced SDHA deficiency combines with high triglyceride to drive the production of reactive oxygen species and subsequent apoptosis during embryonic development, which may account for the occurrence of adverse pregnancy outcomes. Our findings reveal the existence of a hitherto unknown risk of PCSK9i in pregnant women, as well as novel gene-environment interaction.

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