Valproic acid (VPA) is a widely prescribed drug to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, however, exposure to the developing embryo can cause birth defects, cognitive impairment, and autism spectrum disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of VPA drug exposure, including exencephaly, microcephaly, and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial (NE) cells. Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects. Together, these findings demonstrate that misregulated senescence in NE cells can contribute to developmental defects.

Valproic acid (VPA) is widely prescribed to treat epilepsy, bipolar disorder and migraine. However, if taken during pregnancy, exposure to the developing embryo can cause birth defects, cognitive impairment and Autism-Spectrum Disorder. How VPA causes these developmental defects remains unclear. Here, we used embryonic mice and human organoids to model key features of drug exposure, including exencephaly, microcephaly and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find that induction of cellular senescence in neuroepithelial cells is a core feature. Through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but not exencephaly and spinal defects. These findings identify VPA-induced ectopic senescence as a causative mechanism disrupting normal neurodevelopment, illuminating how VPA-exposure during embryonic development can lead to cognitive defects and Autism-Spectrum Disorder.