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Relationship: 2732

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, SHH second messenger production leads to Decrease, Cell proliferation

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 Do not cite Under Development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 Do not cite Under Development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 NCBI
chicken Gallus gallus 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

SHH is a mitogen that regulates cell proliferation during development. SHH regulation of proliferation works at least in part through regulation of cyclin D1 (ccnd 1) and cyclin D2 (Ccnd 2) (Kenney and Rowitch 2000, Ishibashi and McMahon 2002, Lobjois, Benazeraf et al. 2004, Mill, Mo et al. 2005, Hu, Mo et al. 2006). The regulation of ccnd 1 and ccnd 2 by SHH is not fully understood but is believed to be in part by regulation via SHH signaling and its signaling to SHH secondary messengers, namely the fibroblast growth factor family and GLI. GLI1 has been shown to directly bind and regulate ccnd1 and ccnd2 (Yoon, Kita et al. 2002).  A network of reciprocal growth factor signaling between the epithelium and mesenchyme is required for proper growth and patterning of the early palatal shelves. This signaling is largely comprised of a network between bone morphogenic protein (BMP), Fibroblast growth factor (Fgf), and Sonic Hedgehog (SHH) (Zhang, Song et al. 2002, Rice, Spencer-Dene et al. 2004). Activation of the SHH pathway results in a downstream signaling cascade resulting in the relocation of GLI to the nucleus and subsequent gene transcription (Carballo, Honorato et al. 2018). This gene expression drives secondary messenger signaling for the pathway. Proper Msx1 activity in the mesenchyme is required for the expression of SHH in the overlying epithelium (Zhang, Song et al. 2002). Maintenance of SHH expression in the epithelium is believed to be dependent on Fgf10 expression in the mesenchyme and its’ signaling through Fgfr2b in the epithelium (Rice, Spencer-Dene et al. 2004)

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 SHH signaling and secondary messengers and SHH cellular proliferation. 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 2732 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 well known to be associated with cellular proliferation. There is a high biological probability that this proliferation results through regulation of SHH secondary messengers.

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 a decrease is SHH secondary messenger production and a decrease in cellular proliferation is plausible and data is shown that supports a decrease in ccnd 1 and 2 in correlation with the Fgf and SHH pathways.  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
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 in SHH secondary messengers and a decrease in cellular proliferation translocation 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. 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

Alappat, S. R., Z. Zhang, K. Suzuki, X. Zhang, H. Liu, R. Jiang, G. Yamada and Y. Chen (2005). "The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice." Dev Biol 277(1): 102-113.

Carballo, G. B., J. R. Honorato, G. P. F. de Lopes and T. C. L. d. S. e. Spohr (2018). "A highlight on Sonic hedgehog pathway." Cell Communication and Signaling 16(1): 11.

Everson, J. L., D. M. Fink, J. W. Yoon, E. J. Leslie, H. W. Kietzman, L. J. Ansen-Wilson, H. M. Chung, D. O. Walterhouse, M. L. Marazita and R. J. Lipinski (2017). "Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis." Development 144(11): 2082-2091.

Hu, M. C., R. Mo, S. Bhella, C. W. Wilson, P. T. Chuang, C. C. Hui and N. D. Rosenblum (2006). "GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis." Development 133(3): 569-578.

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.

Ohuchi, H., T. Nakagawa, A. Yamamoto, A. Araga, T. Ohata, Y. Ishimaru, H. Yoshioka, T. Kuwana, T. Nohno, M. Yamasaki, N. Itoh and S. Noji (1997). "The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor." Development 124(11): 2235-2244.

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.

Yoon, J. W., Y. Kita, D. J. Frank, R. R. Majewski, B. A. Konicek, M. A. Nobrega, H. Jacob, D. Walterhouse and P. Iannaccone (2002). "Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation." J Biol Chem 277(7): 5548-5555.

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.