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Heterozygous loss-of-function (LoF) variants in , a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of in the human brain is unknown. Here, we studied the impact of deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity.