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Event: 2399

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

FGF10/FGFR2-IIIb signaling in genital tissue, reduced

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Organ term
undifferentiated genital tubercle

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
mesenchymal-epithelial cell signaling	fibroblast growth factor receptor 2	decreased
mesenchymal-epithelial cell signaling	fibroblast growth factor 10	decreased
	fibroblast growth factor 10	decreased
cell activation	fibroblast growth factor 2	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
AR agonism leads to delayed PPS via reduced FGF expression	KeyEvent	Travis Karschnik (send email)	Under development: Not open for comment. Do not cite

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Homo sapiens	Homo sapiens	High	NCBI
guinea pig	Cavia porcellus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Embryo	High
Foetal	High
Fetal to Parturition	High
Development	High

Sex Applicability

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

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

This event describes a decrease in Fibroblast growth factor (FGF) signaling mediated by changes to FGF10 and/or FGFR2-IIIb within genital tissues. It reflects a state in which FGF10 ligand availability is reduced and/or FGFR2-IIIb expression or activation is diminished.

The biological compartment it is measured in are mesenchymal and epithelial cells in genital tissues including GT, preputial lamina, and urethral epithelium (Wang et al., 2025).

FGF10/FGFR2-IIIb signaling plays an essential role in epithelial morphogenesis during external genital development by influencing outgrowth of preputial epithelium, maintenance of epithelial cell processes, and coordination of mesenchymal epithelial interactions required from normal foreskin/clitoral hood formation.

This signaling has been demonstrated to play the same role in other tissues, i.e., lung and palate, as well (Rice et al., 2004; Warburton et al., 2003).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Direct evidence with well validated and widely used techniques that measure ligand/receptor expression and activation.

Expression of FGF10 and FGFR2-IIIb:

RT-qPCR
In situ hybridation
IHC/IF
Western blotting

Receptor activation of FGFR2-IIIb by way of phosphorylation state:

ICH or Western blot
Immunoprecipation followed by phospho-Western blotting

Indirect evidence well validated and widely used techniques that correlate to ligand/receptor expression and activation.

Expression of genes induced by FGF signaling can be measured via:

RT-qPCR
RNA-seq
In situ hybridization

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic Applicability

FGF family and FGF receptors are present and functionally conserved across vertebrates however, their association with external genital development has not been established in non-mammals. This association has been established in mice, humans, and guinea pigs (Wang et al., 2025; Beleza-Meireles et al., 2007; Gredler et al., 2015). SeqAPASS results for taxonomic conservation is attached for FGF10 and FGFR2 as FGF10_SeqAPASS.xlsx and FGFR2_SeqAPASS.xlsx respectively.

Lifestage Applicability

The highest impact of FGF10/FGFR2-IIIb signaling on the development of GT and preputial tissues occurs in embryonic stages, during the period where these structures are established (Harada et al., 2015). It’s plausible that there are residual effects of this signaling in epithelial maturation in the perinatal and postnatal periods based on its role in other tissues (Cui and Li 2013).

Sex Applicability

FGF10/FGFR2-IIIb signaling in genital and pre-cursor tissues occurs in both sexes during development.

References

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

Beleza-Meireles, A., Lundberg, F., Lagerstedt, K., Zhou, X., Omrani, D., Frisén, L., & Nordenskjöld, A. (2007). FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. European Journal of Human Genetics, 15(4), 405-410.

Cui, Y., & Li, Q. (2013). Expression and functions of fibroblast growth factor 10 in the mouse mammary gland. International journal of molecular sciences, 14(2), 4094-4105.

Gredler, M. L., Seifert, A. W., & Cohn, M. J. (2015). Tissue-specific roles of Fgfr2 in development of the external Genitalia. Development, 142(12), 2203-2212.

Harada, M., Omori, A., Nakahara, C., Nakagata, N., Akita, K., & Yamada, G. (2015). Tissue‐specific roles of FGF signaling in external genitalia development. Developmental Dynamics, 244(6), 759-773.

Rice, Ritva, Bradley Spencer-Dene, Elaine C. Connor, Amel Gritli-Linde, Andrew P. McMahon, Clive Dickson, Irma Thesleff, and David PC Rice. "Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate." The Journal of clinical investigation 113, no. 12 (2004): 1692-1700.

Wang, S., & Zheng, Z. (2025). Differences in Formation of Prepuce and Urethral Groove During Penile Development Between Guinea Pigs and Mice Are Controlled by Differential Expression of Shh, Fgf10 and Fgfr2. Cells, 14(5), 348.

Warburton, D., Bellusci, S., Del Moral, P. M., Kaartinen, V., Lee, M., Tefft, D., & Shi, W. (2003). Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry. Respiratory research, 4(1), 5.