API

Relationship: 1808

Title

?

Altered differentiation leads to Neural tube defects

Upstream event

?

Altered differentiation

Downstream event

?


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

Taxonomic Applicability

?

Sex Applicability

?

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

?


Biological Plausibility

?

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.

Empirical Evidence

?

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

?


Response-response Relationship

?

Time-scale

?

Known modulating factors

?

Known Feedforward/Feedback loops influencing this KER

?

Domain of Applicability

?


References

?


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.