Summary: Valproic acid (VPA), an anti-convulsant medication, can cause birth defects when taken during pregnancy. Researchers identified a molecule called p19Arf that appears to be responsible for VPA’s induced senescence in neuroepithelial cells. When exposed to VPA, mice lacking p19Arf did not experience gene expression alterations associated with ASD.
Valproic acid—a drug used to treat epilepsy, migraine, and bipolar disorder—can cause birth defects when taken during pregnancy.
Now, a study published in PLOS Biology by Bill Keyes of the Institute of Genetics and Molecular and Cellular Biology, France, and colleagues reveals one reason why: valproic acid (VPA) puts some cells of the developing nervous system into senescence, a kind of halted state that keeps them from growing and dividing correctly.
VPA is widely used to treat a number of illnesses. However, since its initial use, there have been many thousands of cases of women taking VPA during pregnancy and subsequently giving birth to children with birth defects, including spina bifida, facial alterations, and heart malformation.
In addition, about a third of exposed infants develop cognitive impairment and Autism Spectrum Disorder.
In the new study, Keyes and colleagues used both human organoids—three-dimensional clusters of human cells grown in the lab—as well as mice to study embryonic exposure to VPA. They discovered that VPA induces cellular senescence in neuroepithelial cells, the stem cells that give rise to the central nervous system.
Moreover, the researchers pinpointed one particular molecule, p19Arf, as being responsible for this VPA-induced senescence.
When the team used mice lacking p19Arf, VPA exposure during pregnancy no longer caused microcephaly (small head size) or changes to gene expression patterns associated with Autism Spectrum Disorder, although VPA did lead to other defects even in these mice.
The work is one of the first to associate cellular senescence with developmental defects, the authors say. “Overall, the discovery that atypical activation of senescence in the embryo can perturb development raises the intriguing possibility that it may also contribute to defects in developmental contexts beyond those we studied here.”
Muriel Rhinn, first author of the study, adds, “While cellular senescence has long been associated with aging and age-related disease, we now show that aberrant induction of senescence can also contribute to developmental defects.
“As valproic acid is strongly linked to cognitive defects and Autism Spectrum Disorder, this study now introduces an exciting link with senescence, supporting how additional studies are needed.”
About this neurodevelopment research news
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Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects
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.