摘要：SummaryOptic atrophy 1 (OPA1), a GTPase at the inner mitochondrial membrane involved in regulating mitochondrial fusion, stability, and energy output, is known to be crucial for neural development:Opa1heterozygous mice show abnormal brain development, and inactivating mutations in OPA1 are linked to human neurological disorders. Here, we used genetically modified human embryonic and patient-derived induced pluripotent stem cells and reveal thatOPA1haploinsufficiency leads to aberrant nuclear DNA methylation and significantly alters the transcriptional circuitry in neural progenitor cells (NPCs). For instance, expression of the forkhead box G1 transcription factor, which is needed for GABAergic neuronal development, is repressed inOPA1+/−NPCs. Supporting this finding,OPA1+/− NPCs cannot give rise to GABAergic interneurons, whereas formation of glutamatergic neurons is not affected. Taken together, our data reveal that OPA1 controls nuclear DNA methylation and expression of key transcription factors needed for proper neural cell specification.Graphical AbstractDisplay OmittedHighlights•OPA1haploinsufficiency impairs formation of DLX1/2-positive GABAergic neurons•Reduced OPA1 levels significantly alter the transcriptional circuitry in neural cells•Expression of the pioneer factorFOXG1is decreased inOPA1+/−neural progenitor cells•ImpairedFOXG1expression correlates with increased CpG methylation at its promoterNeurogenetics; Developmental Neuroscience
