Homo sapiens Transcriptome or Gene expression
Development of human embryonic stem cells (hESCs) technology provides a powerful tool tounderstand the mechanism of various diseases, as well as a model for human developmentalstudy in vitro. In this study, we generated neurons from hESCs with previously establishedprotocol and we observed that autophagy-related genes were upregulated at neuroepithelial/NPCstage. To check the importance of autophagy activation, bafilomycin was treated at a specifictime 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 markerNESTIN. Further investigation revealed that WNT signaling might be involved as part of theunderlying mechanisms. Autophagy negatively regulates WNT signaling by promotingDisheveled-2 (DVL-2) degradation. Disruption of autophagy might lead to failure in thedownregulation 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 Vicisyndrome by introducing loss of function mutation in EPG5 gene. Mutation in EPG5 genedisturbed autophagy process, subsequently induced defect in progenitor cells migration andcortical layer generation in organoids. The results showed how damaged autophagy leads tosmaller organoids, recapitulating Vici syndrome-associated microcephaly, and thereforevalidating the disease relevance of our study.