NR2F1 is a cross-species mediator of cerebral cortex defects induced by fetal alcohol exposure

Prenatal alcohol exposure (PAE) remains the leading preventable cause of neurodevelopmental disorders, contributing to a spectrum of cognitive, sensory, and behavioral deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). To date, the precise mechanisms by which PAE disrupts brain development remain unclear, limiting the development of targeted therapies and effective prevention strategies. Alcohol is particularly harmful to the cerebral cortex, and individuals with FASD frequently exhibit impaired sensorimotor function, including deficits in tactile perception.
Using a mouse model of voluntary binge-like alcohol consumption during gestation, we demonstrate that PAE disrupts the migration and connectivity of callosal projection neurons in the developing somatosensory cortex and induces long-lasting sensory deficits. We identified NR2F1, a key transcription factor involved in neuronal migration and cortical patterning, as a novel alcohol-sensitive target mediating these effects. Mechanistically, PAE leads to upregulation of NR2F1, together with downregulation of its direct targets Lis1 and Kif1b, which are essential for neuronal migration and differentiation.

Importantly, these molecular alterations are conserved in the developing cortex of human fetuses with documented prenatal alcohol exposure, as well as in human cerebral organoids engrafted into ethanol-exposed mice. Together, our findings reveal a conserved molecular and cellular pathway disrupted by PAE, highlight NR2F1 as a key regulator in the pathogenesis of FASD, and suggest new avenues for therapeutic intervention targeting alcohol-induced neurodevelopmental impairments.