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

Wang, Fang; Xu, Cheng; Reece, E. Albert; Li, Xuezheng; Wu, Yanqing; Harman, Christopher; Yu, Jingwen; Dong, Daoyin; Wang, Cheng; Yang, Penghua; Zhong, Jianxiang

doi:10.1038/ncomms15182

Cited by 75 publications

(92 citation statements)

References 65 publications

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“…The transgene DN FoxO3a, along with a separate cell nucleus localized GFP, were driven by the Nestin promoter from E8.0 onward. 5 GFP localized in the nucleus confirmed neuroepithelium-specific expression of the transgenes (Figure 3, B). The NTD rate in DN FoxO3a embryos was significantly lower than in WTembryos under maternal diabetic conditions (Figure 2, C and D, and Table 2).…”

Section: Resultssupporting

confidence: 57%

“…5 Cellular organelle stress, including proapoptotic kinase activation, endoplasmic reticulum stress, and autophagy impairment, has been shown to occur in the developing neuroepithelium exposed to maternal diabetes. 5,11–14 Autophagy, an intracellular catabolic process, removes dysfunctional protein aggregates and damaged cellular organelles, and thus maintains intracellular homeostasis. The autophagy process starts with the formation of double membrane vacuoles, called “autophagosomes,” which requires a group of proteins derived from autophagy-related genes (Atgs).…”

Section: Introductionmentioning

confidence: 99%

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The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

Chen

Reece

et al. 2019

American Journal of Obstetrics and Gynecology

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BACKGROUND: Maternal diabetes induces neural tube defects and stimulates the activity of the forkhead box O3 (Fox)O3a in the embryonic neuroepithelium. We previously demonstrated that deleting the FOXO3a gene ameliorates maternal diabetes-induced neural tube defects. Macroautophagy (hereafter referred to as “autophagy”) is essential for neurulation. Rescuing autophagy suppressed by maternal diabetes in the developing neuroepithelium inhibits neural tube defect formation in diabetic pregnancy. This evidence suggests a possible link between FoxO3a and impaired autophagy in diabetic embryopathy. OBJECTIVE: We aimed to determine whether maternal diabetes suppresses autophagy through FoxO3a, and if the transcriptional activity of FoxO3a is required for the induction of diabetic embryopathy. STUDY DESIGN: We used a well-established type 1 diabetic embryopathy mouse model, in which diabetes was induced by streptozotocin, for our in vivo studies. To determine if FoxO3a mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium, we induced diabetic embryopathy in FOXO3a gene knockout mice and FoxO3a dominant negative transgenic mice. Embryos were harvested at embryonic day 8.5 to determine FoxO3a and autophagy activity and at embryonic day 10.5 for the presence of neural tube defects. We also examined the expression of autophagy-related genes. C17.2 neural stem cells were used for in vitro examination of the potential effects of FoxO3a on autophagy. RESULTS: Deletion of the FOXO3a gene restored the autophagy markers, lipidation of microtubule-associated protein 1A/1B-light chain 3I to light chain 3II, in neurulation stage embryos. Maternal diabetes decreased light chain 3I-positive puncta number in the neuroepithelium, which was restored by deleting FoxO3a. Maternal diabetes also decreased the expression of positive regulators of autophagy (Unc-51 like autophagy activating kinase 1, Coiled-coil myosin-like BCL2-interacting protein, and autophagy-related gene 5) and the negative regulator of autophagy, p62. FOXO3a gene deletion abrogated the dysregulation of autophagy genes. In vitro data showed that the constitutively active form of FoxO3a mimicked high glucose in repressing autophagy. In cells cultured under high-glucose conditions, overexpression of the dominant negative FoxO3a mutant blocked autophagy impairment. Dominant negative FoxO3a overexpression in the developing neuroepithelium restored autophagy and significantly reduced maternal diabetes-induced apoptosis and neural tube defects. CONCLUSION: Our study revealed that diabetes-induced FoxO3a activation inhibited autophagy in the embryonic neuroepithelium. We also observed that FoxO3a transcriptional activity mediated the teratogenic effect of maternal diabetes because dominant negative FoxO3a prevents maternal diabetes-induced autophagy impairment and neural tube defect formation. Our findings suggest that autophagy activators could be therapeutically effective in treating maternal diabetes-induced neural tube def...

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Section: Resultssupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

Chen

Reece

et al. 2019

American Journal of Obstetrics and Gynecology

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“…In the presence of NH 4 Cl, the ratio of LC3B II/I tended to increase in HG‐treated NSCs. However, a recent study reported that HG inhibited E10.5 brain autophagy in vivo . Our explanation for this discrepancy is as following: (a) we used NSCs mainly at E11.5 and (b) we examined the relationship between autophagy and HG in vitro and autophagic flux could be easily blocked, but autophagic flux was hardly blocked in vivo.…”

Section: Discussionmentioning

confidence: 94%

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Zhang

Liu

et al. 2019

Stem Cells

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Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. STEM CELLS 2019;37:504-515 SIGNIFICANCE STATEMENTNeural stem cells play important roles in fetal neurodevelopment. The incidences of gestational diabetes are rising in the world and prevention of fetal neuropathy in gestational diabetes mellitus (GDM) needs to be deeply explored. In addition, autophagy of NSCs in HG is still unclear. Here, it is reported that HG inhibits proliferation and induces premature differentiation of NSCs by promoting autophagy and autophagic flux. The naturally occurring hormone melatonin (Mel) antagonized HG-mediated effects and maintained normal proliferation and differentiation in NSCs by modulating autophagy, which protected NSCs mainly by downregulating Beclin-1 and up modulating mTORC1 signaling. This work indicates that Mel could be used as a potential drug to aid in fetal central nervous system (CNS) development in GDM patients.

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“…The ApopTag Red In Situ Apoptosis Detection Kit (Millipore) was used to detect apoptotic cells as previously described(Wang et al , 2017). Briefly, formalin-fixed brain tissues were dehydrated by series of 50%–100% ethanol and then embedded in paraffin for sectioning.…”

Section: Methodsmentioning

confidence: 99%

Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

et al. 2018

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Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism.

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

Cited by 75 publications

References 65 publications

The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

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