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.
Highlights
Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy
Maternal diabetes induced a various types of NTDs including exencephaly, craniorachischisis and spina bifida (Supplementary Fig. 1A)
These findings suggest that apoptosis has to reach a threshold for NTD formation, and neuroepithelial cell apoptosis in normal embryos from diabetic dams may be related to microcephaly
Summary
Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy. PGC-1a supports neurulation by stimulating autophagy in neuroepithelial cells These findings identify two negative autophagy regulators, PKCa and miR-129-2, which mediate the teratogenicity of hyperglycaemia leading to NTDs. We reveal a function for PGC-1a in embryonic development through promoting autophagy and ameliorating hyperglycaemia-induced NTDs. Incomplete neural tube closure results in neural tube defects (NTDs), severe birth defects of the central nervous system (CNS)[1]. Autophagy is required for embryonic neurulation because autophagy deficiency in Autophagy/beclin-1 regulator 1 (AMBRA1) null mutants results in massive neuroepithelial cell apoptosis and NTDs7, reminiscent of those observed in diabetic embryopathy It is unclear how maternal diabetes represses autophagy during neurulation in the developing neuroepithelium. Our study revealed two negative autophagy regulators under maternal diabetic conditions, and provided a basis for potential therapeutic interventions for maternal diabetes-induced NTDs by targeting PKCa or miR-129-2 or enhancing PGC-1a activities
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