Aberrant induction of p19^Arf-mediated cellular senescence contributes to neurodevelopmental defects

Abstract

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.

How can same-gene mutations promote both cancer and developmental disorders?

“…p19 ARF and p16 INK4A are critical mediators of cellular senescence ( 93 , 94 ). Recent data suggest that p19 ARF can also be among the proteins taking part in senescence during embryonic development, albeit through a different scenario ( 95 ). Valproic acid induces p19 ARF -mediated cellular senescence causing neurodevelopmental defects including cognitive defects and autism.…”