GSE132965
The imbalance of excitatory/inhibitory neuron differentiation in neurodevelopmental disorders with an NR2F1 point mutation
Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features, and investigate their neurodevelopmental alterations. Mut hESCs overproduce ventral telencephalic neuron progenitors (ventral NPCs) and inhibitory neurons, and underproduce dorsal NPCs and excitatory neurons. These alterations can be mainly attributed to the aberrantly activated Hedgehog signaling pathway. Moreover, the corresponding Nr2f1 point mutant mice display a similar excitatory/inhibitory neuron imbalance and abnormal behaviors. Antagonizing the increased inhibitory synaptic transmission partially alleviates their behavioral deficits. Together, our results suggest that the NR2F1-dependent imbalance of excitatory/inhibitory neuron differentiation caused by the activated Hedgehog pathway is one precursor of neurodevelopmental disorders and may enlighten the therapeutic approaches. Overall design: WT and Mut human NPCs were subjected into transcriptome analysis with two biological replicates. ChIP-Seq was done by over-expressing an equal amount of pcDNA3.1-WT/Mut-NR2F1-Flag plasmids into WT hESC-derived neuron progenitors with two biological replicates, and the DNA-protein complex was precipitated by Flag beads.