This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Relationship: 2726
Title
Decrease, outgrowth leads to OFC
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Antagonism of Smoothened receptor leading to orofacial clefting | adjacent | Moderate | Low | Arthur Author (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decrease, GLI1/2 target gene expression leads to orofacial clefting | adjacent | Moderate | Low | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mouse | Mus musculus | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific |
Life Stage Applicability
Term | Evidence |
---|---|
Embryo | High |
Key Event Relationship Description
Orofacial clefts (OFCs) are one of the most common human birth defects and occur in approximately 1 in 700 live births (Mossey, Little et al. 2009, Dixon, Marazita et al. 2011). Formation of the upper lip and palate requires the orchestrated proliferation and fusion of embryonic facial growth centers and is dependent on paracrine intercellular signaling through multiple pathways. Genetic and chemical disruption of the Sonic Hedgehog (SHH), Transforming growth factor-beta (Tgf-β), bone morphogenic protein (BMP), epidermal growth factor (EGF) etc. pathways have been shown to cause OFCs (Jiang, Bush et al. 2006, Bush and Jiang 2012, Lan, Xu et al. 2015). Early orofacial development involves epithelial ectoderm derived SHH ligand driving tissue outgrowth through an induced gradient of SHH dependent transcription in the underlying mesenchyme, which is thought to drive mesenchymal proliferation (Lan and Jiang 2009, Kurosaka 2015).
The development of the face occurs early in embryogenesis and involves precise coordination of multiple tissues. The oropharyngeal membrane appears early in the 4th week of gestation and gives rise to the frontonasal process and the 1st pharyngeal arch. The frontonasal process is derived from the neural crest and in turn gives rise to two medial nasal process and two lateral nasal processes that later fuse and form the intermaxillary process. The pharyngeal arch is derived from mesoderm and the neural crest. It gives rise to two mandibular process and two maxillary processes (Som and Naidich 2013). These processes are comprised of mesenchymal cells from neural crest migration and the craniopharyngeal ectoderm and are coated in an epithelium (Ferguson 1988). The upper lip is formed during weeks 5-7 when the maxillary processes grow towards the midline and fuse intermaxillary process that have formed the philtrum and columella (Warbrick 1960, Kim, Park et al. 2004). The palate develops between week 6-12 from a median palatine process and a pair of lateral palatine processes. The primary palate is formed from the posterior extension of the intermaxillary process. The lateral palatine processes arise as medial mesenchymal processes from both maxillary processes. These processes initially grow inferiorly until the tongue is pulled downwards by the elongation of the maxilla and mandible. Once above the tongue, the lateral processes grow medially until they make contact and fuse (Som and Naidich 2014). For normal facial development and growth coordinated multivariate signaling is required. For example, retinoic acid, BMP, FGF, and SHH signal together to control facial growth (Liu, Rooker et al. 2010). SHH is an important modulator of epithelial-mesenchyme interaction (EMi) during development. SHH has been shown to regulate growth and formation of the palatal shelves prior to elevation and fusion (Rice, Connor et al. 2006). During development, SHH ligand is secreted by the epithelium into the underlying mesenchyme. This causes a gradient of signaling where mesenchyme proximal to the epithelium is exposed to higher concentrations of SHH than more distal cells (Cohen, Kicheva et al. 2015). Disruption of SHH during critical windows of development is believed to work in an EMi dependent, but epithelial-mesenchyme transition (Emt) independent manner. OFCs caused by disruption to SHH are believed to be due to a reduction in epithelial induced proliferation and the subsequent decrease in tissue outgrowth and the failure of the facial processes to meet and fuse (Lipinski, Song et al. 2010, Heyne, Melberg et al. 2015).
Evidence Collection Strategy
Pubmed was used as the primary database for evidence collection. Searches are organized by the date and search terms used in the supplementary table. Search results were initially screened through review of the title and abstract for potential for data relating a decrease in outgrowth and OFC. Each selected publication and its’ data were then examined to determine if support or lack thereof existed for this KER. Papers that did not show any data relating to this KER were discarded. The search terms used are organized below in Table 1.
Evidence Supporting this KER
Biological Plausibility
The SHH pathway is well known to be associated with development of the face including the lip and palatal. Disruption of SHH at critical periods of development has been shown to cause OFCs.
Empirical Evidence
- In vitro
- None identified
- In vivo
- ~85% of K14-Cre;Shhc/n mice had cleft palate with rudimentary palatal shelves spaced apart without contact suggesting that the cleft is due to insufficient outgrowth of the shelves (Rice, Spencer-Dene et al. 2004).
- 100% (n=22) Osr2-IresCre;Smoc/c had a cleft palate. At E14.5 the palatal shelves were underdeveloped and had not grown out to make contact compared to control littermates that had met and initiated fusion. This supports that disruption of SHH signalling impairs palatal shelf outgrowth and can lead to cleft palate (Lan and Jiang 2009)
Uncertainties and Inconsistencies
The quantitative understanding of this relationship is low. No studies were found to exist to address dose response or time-scale data. Further work is needed to address these questions and create a better understanding of this relationship.
Known modulating factors
Quantitative Understanding of the Linkage
The quantitative understanding of this relationship is low. No studies were found to exist to address dose response or time-scale data. Further work is needed to address these questions and create a better understanding of this relationship.
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship is biologically plausible in human, but to date no specific experiments have addressed this question. The SHH pathway is well understood to be fundamental to proper embryonic development and that aberrant SHH signaling during embryonic development can cause birth defects including orofacial clefts (OFCs). For this reason, this KER is applicable to the embryonic stage with a high level of confidence.
References
Bush, J. O. and R. Jiang (2012). "Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development." Development 139(2): 231-243.
Cohen, M., A. Kicheva, A. Ribeiro, R. Blassberg, K. M. Page, C. P. Barnes and J. Briscoe (2015). "Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms." Nature Communications 6(1): 6709.
Dixon, M. J., M. L. Marazita, T. H. Beaty and J. C. Murray (2011). "Cleft lip and palate: understanding genetic and environmental influences." Nature Reviews Genetics 12(3): 167-178.
Ferguson, M. W. (1988). "Palate development." Development 103 Suppl: 41-60.
Heyne, G. W., C. G. Melberg, P. Doroodchi, K. F. Parins, H. W. Kietzman, J. L. Everson, L. J. Ansen-Wilson and R. J. Lipinski (2015). "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate." PLoS One 10(3): e0120517.
Jiang, R., J. O. Bush and A. C. Lidral (2006). "Development of the upper lip: morphogenetic and molecular mechanisms." Dev Dyn 235(5): 1152-1166.
Kim, C. H., H. W. Park, K. Kim and J. H. Yoon (2004). "Early development of the nose in human embryos: a stereomicroscopic and histologic analysis." Laryngoscope 114(10): 1791-1800.
Kurosaka, H. (2015). "The Roles of Hedgehog Signaling in Upper Lip Formation." Biomed Res Int 2015: 901041.
Lan, Y. and R. Jiang (2009). "Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth." Development 136(8): 1387-1396.
Lan, Y., J. Xu and R. Jiang (2015). "Cellular and Molecular Mechanisms of Palatogenesis." Curr Top Dev Biol 115: 59-84.
Lipinski, R. J., C. Song, K. K. Sulik, J. L. Everson, J. J. Gipp, D. Yan, W. Bushman and I. J. Rowland (2010). "Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications." Birth Defects Res A Clin Mol Teratol 88(4): 232-240.
Liu, B., S. M. Rooker and J. A. Helms (2010). "Molecular control of facial morphology." Semin Cell Dev Biol 21(3): 309-313.
Mossey, P. A., J. Little, R. G. Munger, M. J. Dixon and W. C. Shaw (2009). "Cleft lip and palate." The Lancet 374(9703): 1773-1785.
Rice, R., E. Connor and D. P. C. Rice (2006). "Expression patterns of Hedgehog signalling pathway members during mouse palate development." Gene Expression Patterns 6(2): 206-212.
Rice, R., B. Spencer-Dene, E. C. Connor, A. Gritli-Linde, A. P. McMahon, C. Dickson, I. Thesleff and D. P. Rice (2004). "Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate." J Clin Invest 113(12): 1692-1700.
Som, P. M. and T. P. Naidich (2013). "Illustrated review of the embryology and development of the facial region, part 1: Early face and lateral nasal cavities." AJNR Am J Neuroradiol 34(12): 2233-2240.
Som, P. M. and T. P. Naidich (2014). "Illustrated review of the embryology and development of the facial region, part 2: Late development of the fetal face and changes in the face from the newborn to adulthood." AJNR Am J Neuroradiol 35(1): 10-18.
Warbrick, J. G. (1960). "The early development of the nasal cavity and upper lip in the human embryo." J Anat 94(Pt 3): 351-362.