Upstream eventAltered differentiation
Neural tube defects
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leads to neural tube defects||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
During the process of neural tube closure, the cells at the dorsal boundary a new cell type arises, the neural crest cells. These cells undergo an epithelial to mesenchymal transition that enables them to migrate away from the neural tube. If the neuroepithelial cells of the neural tube express the wrong regulator genes it may happen that they acquire such neural crest characteristics, which prevents them from performing the closure of the neural tube.
Evidence Supporting this KER
Many HDAC inhibitors used as drugs have been shown to induce congenital malformations, including neural tube closure defects in humans and model organisms (Menegola et al., 1996; Nau, 1994). Most studies show that after treatment with HDAC inhibitors these malformations occur in the experimental animals, however direct evidence that neural tube closure defects result from wrongly differentiated neural tube cells.
TSA treated chicken embryos showed a disturbed gene expression pattern of the posterior neural tube, that points to a wrong differentiation track towards neural crest cells. This was shown by in situ immune staining using neural crest-specific antibodies (Murko et al., 2013).
Further Menegola et al. showed direct evidence that HDAC inhibition is occurring in vivo in the neural tube of mice (Menegola et al., 2005).
Uncertainties and Inconsistencies
Due to lacking studies directly showing that the neural tube cells are wrongly differentiated and that this may causative for closure defects the uncertainty of this KER is very high and based on correlation studies.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Menegola, E., Broccia, M. L., Nau, H. et al. (1996). Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratog Carcinog Mutagen 16, 97-108. doi:10.1002/(SICI)1520-6866(1996)16:2<97::AID-TCM4>3.0.CO;2-A
Menegola, E., Di Renzo, F., Broccia, M. L. et al. (2005). Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol 74, 392-398. doi:10.1002/bdrb.20053
Murko, C., Lagger, S., Steiner, M. et al. (2013). Histone deacetylase inhibitor trichostatin a induces neural tube defects and promotes neural crest specification in the chicken neural tube. Differentiation 85, 55-66. doi:10.1016/j.diff.2012.12.001
Nau, H. (1994). Valproic acid-induced neural tube defects. Ciba Found Symp 181, 144-152; discussion 152-160.