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Relationship: 2722

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 Decrease, Cell proliferation

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

Decrease, Cell proliferation

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

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
human	Homo sapiens	Low	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

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

SHH is well understood to regulate cell proliferation during development. Shh regulation of proliferation works at least in part through regulation of cyclin D1 (Ccnd 1) and Ccnd 2 (Kenney and Rowitch 2000, Ishibashi and McMahon 2002, Lobjois, Benazeraf et al. 2004, Mill, Mo et al. 2005).

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

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

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 vivo
- In mouse palate explants application of SHH was found to induce proliferation in the palatal mesenchyme as measured by BrdU (Rice, Spencer-Dene et al. 2004).
- In CD-1 WT and MSX-1-/-, SHH soaked beads were able to induce proliferation in palatal mesenchyme explants at 24hr but not after 8hr suggesting the induction of proliferation is through an indirect mechanism (Zhang, Song et al. 2002).
- IHC staining for Ccnd-1 and Ccnd-2 in Osr2-IresCre Smo^c/c (SHH inactive)and control embryos was used to determine if expression patterns differed between the mesenchyme and epithelium in mutants. Expression for both Ccnd-1 and Ccnd-2 was found to be reduced in the mesenchyme for mutants. mRNA was found to be reduced for both Ccnd-1 and Ccnd-2 in the palatal mesenchyme (Lan and Jiang 2009).

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 regulation of proliferation by shh and its’ regulation of ccnd-1 and ccnd-2 has not been well studied. The relationship is biologically plausible and the studies presented suggest that some of the regulation of proliferation is due to gene expression of ccnd-1, ccnd-2. Further studies are needed to further out understanding of the regulation of proliferation by shh.

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

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 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

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

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

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 SHH second messengers and a decrease in proliferation has been shown repeatedly 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.

References

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

Ishibashi, M. and A. P. McMahon (2002). "A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo." Development 129(20): 4807-4819.

Kenney, A. M. and D. H. Rowitch (2000). "Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors." Mol Cell Biol 20(23): 9055-9067.

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

Lobjois, V., B. Benazeraf, N. Bertrand, F. Medevielle and F. Pituello (2004). "Specific regulation of cyclins D1 and D2 by FGF and Shh signaling coordinates cell cycle progression, patterning, and differentiation during early steps of spinal cord development." Dev Biol 273(2): 195-209.

Mill, P., R. Mo, M. C. Hu, L. Dagnino, N. D. Rosenblum and C. C. Hui (2005). "Shh controls epithelial proliferation via independent pathways that converge on N-Myc." Dev Cell 9(2): 293-303.

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.

Zhang, Z., Y. Song, X. Zhao, X. Zhang, C. Fermin and Y. Chen (2002). "Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis." Development 129(17): 4135-4146.