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Key Event Title
Neural crest cell migration, reduced
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|HDAC inhibition leads to impeded craniofacial development||KeyEvent||Marvin Martens (send email)||Open for adoption|
Key Event Description
Neural crest cell (NCC) migration is dependent on coordinated expressional alterations of a large number of genes, such as integrins, matrix metalloproteinases, and cytoskeletal components.
The differential regulation of a panel of such genes, has been investigated in an in vitro system, which found that histone deacetylases VPA, TSA, and SAHA exerted similar gene regulatory profiles which were quite distinct from those of other compounds shown to affect NCC migration in a scratch assay (Dreser et al., 2015). A similar experimental setup has applied a broader Affymetrix chip approach to identify biomarkers specific to the inhibition of NCC migration (Pallocca et al., 2016). In vivo evidence for the importance of specific HDACs to NCC migration has been provided by genetic knock down experiments in zebrafish embryos (DeLaurier et al., 2012).
It is likely that the NCC migratory inhibition exerted by HDAC inhibitors is, at least in part, due to the broad transcriptomic impact of HDAC action on histones. However, it cannot be excluded HDAC inhibition could, to some degree, be effects altered acetylation patterns on other proteins, e.g. tubulin acetylation has been shown to be affected by HDAC activity (Hubbert et al., 2002).
How It Is Measured or Detected
NCC migration can be assessed in vitro by scratch assays, and in vivo in developing zebrafish embryos by confocal microscopy with the sox10 fluorescent reporter fishline. Sox10 is a recognized marker of migratory NCCs (Britsch et al., 2001).
Domain of Applicability
Britsch, S., Goerich, D.E., Riethmacher, D., Peirano, R.I., Rossner, M., Nave, K.A., et al. (2001), Genes Dev 15: 66–78.
DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16.
Dreser, N., Zimmer, B., Dietz, C., Sügis, E., Pallocca, G., Nyffeler, J., et al. (2015), Neurotoxicology 50: 56–70.
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002), Nature 417: 455–458.
Pallocca, G., Grinberg, M., Henry, M., Frickey, T., Hengstler, J.G., Waldmann, T., et al. (2016), Arch Toxicol 90: 159–180.