Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy

Fang Wang, Cheng Xu, E. Albert Reece, Xuezheng Li, Yanqing Wu, Christopher Harman, Jingwen Yu, Daoyin Dong, Cheng Wang, Penghua Yang, Jianxiang Zhong and Peixin Yang ()
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Fang Wang: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Cheng Xu: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
E. Albert Reece: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Xuezheng Li: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Yanqing Wu: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Christopher Harman: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Jingwen Yu: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Daoyin Dong: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Cheng Wang: Gynecology, Nebraska Medical Center
Penghua Yang: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Jianxiang Zhong: Gynecology & Reproductive Sciences, University of Maryland School of Medicine
Peixin Yang: Gynecology & Reproductive Sciences, University of Maryland School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy. Here we report the key autophagy regulators modulated by diabetes in the murine developing neuroepithelium. Diabetes predominantly leads to exencephaly, induces neuroepithelial cell apoptosis and suppresses autophagy in the forebrain and midbrain of NTD embryos. Deleting the Prkca gene, which encodes PKCα, reverses diabetes-induced autophagy impairment, cellular organelle stress and apoptosis, leading to an NTD reduction. PKCα increases the expression of miR-129-2, which is a negative regulator of autophagy. miR-129-2 represses autophagy by directly targeting PGC-1α, a positive regulator for mitochondrial function, which is disturbed by maternal diabetes. PGC-1α supports neurulation by stimulating autophagy in neuroepithelial cells. These findings identify two negative autophagy regulators, PKCα and miR-129-2, which mediate the teratogenicity of hyperglycaemia leading to NTDs. We also reveal a function for PGC-1α in embryonic development through promoting autophagy and ameliorating hyperglycaemia-induced NTDs.

Date: 2017
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DOI: 10.1038/ncomms15182

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