Intellectual disability risk gene RFX4 regulates cortical neurogenesis by restraining neuronal differentiation

RFX4 deficiency in human cortical organoids persistently dysregulates neuronal differentiation by repressing pro-neuronal gene expression, while leaving direct-differentiation–generated neurons unaffected.

• Why it matters: RFX4 was recently linked to neurodevelopmental disorders, but its specific functions in cortical development and how pathogenic variants act were unclear.
• What they did: Using human stem cell models with RFX4 deficiency and pathogenic mutation, the study tested cortical organoid neurogenesis and defined chromatin recruitment, including RFX3 recruitment by RFX4 to regulate synaptic and activity-dependent gene expression.
• The result: RFX4 restrains neurogenesis during cortical inhibitory neuron development and supports lineage-specific control of proliferation; DNA-binding–domain mutation reduces DNA binding and dysregulates gene expression differently from deficiency, suggesting a distinct pathogenic mechanism.

AI summary of the abstract · may contain errors · not medical advice · read the paper.