Upstream eventReduced neural crest cell migration
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||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. NCCs are progenitors of several different tissues and cell types, and their precise fate is regulated in a complex manner with influences from surrounding epithelial tissues (Bhatt et al., 2013). The migration and condensation of NCCs at their proper location is a prerequisite to their differentiation and collagen production.
Evidence Supporting this KER
The ultimate fate of the multipotent NCCs is only settled after migration and is controlled in a complex interplay of intrinsic and external signal cues. The overall migration patterns are well established and are conserved across vertebrates (Kulesa et al., 2004). Though the regulation is complex and there are gaps in our understanding, factors governing the overall NCC migration patterns and chondrogenic differentiation are fairly well understood (Bhatt et al., 2013; Hall, 2014). The defining trait of differentiated chondrocytes is the expression of collagen 2a, controlled by the transcription factor Sox9 (Ng et al., 1997; Mori-Akiyama et al., 2003). Sox9 is again controlled in a tissue-dependent manner through the actions of Hox genes and fibroblast growth factors (Trainor and Krumlauf, 2001) in order to define the structural features of the face.
In palatal development it has been shown that suppressed cranial NCC migration and subsequent reductions in NCC populations fail to recover at the post-migratory stage and that this suppressed NCC phenotype correlates with later cartilaginous defects (DeLaurier et al., 2012).
Uncertainties and Inconsistencies
Critical numbers of NCC migrating to their destination has been shown to be an important factor in the development of other NCC derived tissues and cell systems (Barlow et al., 2008), but, to the best of our knowledge, this has not been shown directly in facial cartilage development.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Bhatt, S., Diaz, R., Trainor, P. a, Wu, D.K., Kelley, M.W., Tam, P.L., et al. (2013), Cold Spring Harb Perspect Biol 5: 1–20.
DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16.
Hall, B.K. (2014), Am J Med Genet Part A 164: 884–891.
Kulesa, P., Ellies, D.L., and Trainor, P.A. (2004), Dev Dyn 229: 14–29.
Mori-Akiyama, Y., Akiyama, H., Rowitch, D.H., and Crombrugghe, B. de (2003), Proc Natl Acad Sci 100: 9360–9365
Ng, L.-J., Wheatley, S., Muscat, G.E.., Conway-Campbell, J., Bowles, J., Wright, E., et al. (1997), Dev Biol 183: 108–121
Trainor, P.A., and Krumlauf, R. (2001), Curr Opin Cell Biol 13: 698–705.