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Relationship: 2792


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Apoptosis leads to Decrease, outgrowth

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Low Low Jacob Reynolds (send email) Under development: Not open for comment. Do not cite Under Development
Decrease, GLI1/2 target gene expression leads to orofacial clefting adjacent Low Low Jacob Reynolds (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Embryo High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 decrease in cellular proliferation and an increase in apoptosis leading to a 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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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 cellular death (apoptosis) and outgrowth. 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.

Table 1: KER 2792 literature search

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The SHH pathway is known to be associated with cell survival and that disruption of SHH signaling can lead to increased apoptosis. There is a high biological plausibility that increased apoptosis would lead to decreased palatal shelf outgrowth.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The exact mechanism through which SHH promotes cell survival is not well understood. Further studies are needed to illuminate the mechanism that links SHH signaling with cell survival.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)

Insufficient evidence

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Insufficient evidence

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Insufficient evidence

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Insufficient evidence

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The relationship between an increase in apoptosis and a decrease in palatal shelf outgrowth has been shown in mice models as detailed in the empirical evidence section. 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.  


List of the literature that was cited for this KER description. More help

Ahlgren, S. C., V. Thakur and M. Bronner-Fraser (2002). "Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure." Proc Natl Acad Sci U S A 99(16): 10476-10481.

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.

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.

Jeong, J., J. Mao, T. Tenzen, A. H. Kottmann and A. P. McMahon (2004). "Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia." Genes Dev 18(8): 937-951.

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.

Lan, Y. and R. Jiang (2009). "Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth." Development 136(8): 1387-1396.

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.

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.

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.