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Autophagy regulates neuronal differentiation by controlling WNT/DVL signal pathway

ABSTRACT: Development of human embryonic stem cells (hESCs) technology provides a powerful tool to understand the mechanism of various diseases, as well as a model for human developmental study in vitro. In this study, we generated neurons from hESCs with previously established protocol and we observed that autophagy-related genes were upregulated at neuroepithelial/NPC stage. To check the importance of autophagy activation, bafilomycin was treated at a specific time point. We found that inhibition of autophagy at NPC stage delayed neuronal differentiation, as indicated by the downregulation of neuronal marker TUJ1 and upregulation of NPC marker NESTIN. Further investigation revealed that WNT signaling might be involved as part of the underlying mechanisms. Autophagy negatively regulates WNT signaling by promoting Disheveled-2 (DVL-2) degradation. Disruption of autophagy might lead to failure in the downregulation of WNT signaling and consequently, delaying neuronal differentiation. Dysregulation of autophagy has been associated with a variety of neurological diseases, including Vici syndrome. Here, we developed cerebral organoids culture to model Vici syndrome by introducing loss of function mutation in EPG5 gene. Mutation in EPG5 gene disturbed autophagy process, subsequently induced defect in progenitor cells migration and cortical layer generation in organoids. The results showed how damaged autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and therefore validating the disease relevance of our study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240920 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9 M-BM-5M or 0 to 40M-BM-5g/dl) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural precursor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9 M-BM-5M or 40M-BM-5g/dl Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChipM-BM-. demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development. We analyzed the methylation profile of undifferentiated (n=2 independent experiments) and differentiating (n=2 independent experiments) human embryonic stem cells (hESCs) acutely exposed to losed to lead (Pb) and neural precursor cells derived from hESCs chronically exposed to Pb throughout the neural differentiation process (n=3 independent experiments).

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Autophagy regulates neuronal differentiation by controlling WNT/DVL signal pathway

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