Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

• Published in: PLoS biology 2022-06, Vol.20 (6), p.e3001664-e3001664
• Main Authors: Rhinn, Muriel, Zapata-Bodalo, Irene, Klein, Annabelle, Plassat, Jean-Luc, Knauer-Meyer, Tania, Keyes, William M
• Format: Article
• Language: English
• Subjects: Acids; Aging; Apoptosis; Autism; Biology and Life Sciences; Bipolar disorder; Birth defects; Brain; Cell cycle; Cell growth; Cognitive ability; Congenital defects; Disease; Drug dosages; Embryos; Epilepsy; Exencephaly; Genotype & phenotype; Headache; Medicine and Health Sciences; Microcephaly; Microencephaly; Migraine; Neurogenesis; Organoids; Research and Analysis Methods; Senescence; Spina bifida; Spinal cord; Valproic acid
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001664

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.