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Relationship: 2882

Title

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

Decrease, GLI1/2 target gene expression leads to Apoptosis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, GLI1/2 target gene expression

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Apoptosis

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 Do not cite	Under Review

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
Unspecific

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 GLI transcription factors are the main transcription factors of the Sonic Hedgehog (SHH) pathway. Sonic Hedgehog is a major developmental pathway involved in embryonic development. Disruption of SHH during critical windows of development can cause birth defects (ex. Orofacial clefting (OFCs)). 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). This increase is apoptosis is believed to be due to a decrease in GLI1/2 target gene expression.

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 GLI1 target gene expression and apoptosis. 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 2882 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

There is a high biological probability that disruption of GLI1/2 target gene expression leads to an increase in apoptosis.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In vitro
- None found
In vivo
- Decreased GLI1/2 expression found using in situ hybridization was found on E9.5 embryos of all-trans RA (E 8.5 25mg/kg oral gavage) exposed pregnant dams. An increase in apoptosis of CNCC was also found in the E9.5 embryos. A rescue experiment with SAG (SMO agonist) dosed in combination with RA reduced the incidence of CP and CNCC apoptosis (Wang, Kurosaka et al. 2019).
- Chick embryos exposed to 200µl of 10% ethanol with an additional 20µl of 1% ethanol at stage 9-10 display saw decreased GLI and SHH expression in the head. These embryos also display a reduction in the growth of the frontonasal prominence, hypoplastic branchial arches, and increased apoptosis in cranial neural crest cells. Treatment with antibodies that block SHH signalling had the same impact (Ahlgren, Thakur et al. 2002).

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 relationship between GLI1/2 target gene expression and increased apoptosis has a high biological plausibility although there is currently lack of studies that address this relationship.

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)
Further work is needed to increase the understanding of this relationship and its’ modulating factors.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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

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

Further work is needed to increase the understanding of this relationship and its’ response-response relationship.

Time-scale

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

Further work is needed to increase the understanding of this relationship and its’ time scale.

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

Further work is needed to increase the understanding of this relationship and shed light on what other feedback/forward loops are at play.

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 a decrease in cellular proliferation and a decrease in outgrowth has been demonstrated in both mouse and chick models. The relationship is biologically plausible in human, but to date no specific experiments have addressed this question.

References

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.

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.

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.

Wang, Q., H. Kurosaka, M. Kikuchi, A. Nakaya, P. A. Trainor and T. Yamashiro (2019). "Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate." Dis Model Mech 12(10).

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.