Upstream eventHistone deacetylase inhibition
Reduced collagen production
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leads to impeded craniofacial development||non-adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
Post-migratory NCCs form the progenitor population from which collagen-secreting chondrocytes develop. In addition to the effects on NCC migration, specific HDACs may affect chondrogenesis by disturbing genetic inducers of chondrogenic differentiation, such as sox9, after NCC migration.
Evidence Supporting this KER
In zebrafish embryos, TSA mediated HDAC inhibition was found to drastically reduce cartilage formation when applied in a 24-hour window from 28 to 52 hours post fertilization (after NCC migration has occurred) (Ignatius et al., 2013). Furthermore a mutant, deficient in HDAC1, display no observable defects in NCC induction or migration (Ignatius et al., 2008), yet is highly attenuated in collagen secretion and development of craniofacial cartilage structures (Ignatius et al., 2013), indication a function for specific HDACs in chondrogenesis which is separate from NCC migration.
In ex vivo mouse limbs VPA mediated chemical HDAC inhibition was found to reduce sox9 and collagen type II (col2a1) expression, effects which correlated with reduced limb elongation (Paradis and Hales, 2013).
In zebrafish, chemical HDAC inhibition can attenuate craniofacial cartilage formation after NCC migration is complete (Ignatius et al., 2013).
Uncertainties and Inconsistencies
It is very likely that different HADCs serve different functions in the developing organism. Differences in spatiotemporal expression patterns or sensitivities of individual HDACs to specific chemical inhibitors will need extensive experimental work in order to be fully understood.
At present, it is well established that in developing zebrafish, that at least two HDACs (HDAC1 and HDAC4) are involved in chondrogenic development. But whether those are the only ones, and whether they are equally sensitive to the various classes of HDAC inhibitors remains to be elucidated.
Furthermore, it remains to be shown if the functions of genes identified in zebrafish, translates directly to those in humans.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Ignatius, M.S., Moose, H.E., El-Hodiri, H.M., and Henion, P.D. (2008), Dev Biol 313: 568–583.
Ignatius, M.S., Unal Eroglu, A., Malireddy, S., Gallagher, G., Nambiar, R.M., and Henion, P.D. (2013), PLoS One 8: 1–14.
Paradis, F.H., and Hales, B.F. (2013), Toxicol Sci 131: 234–241.