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Relationship: 3707
Title
FGF10/FGFR2-IIIb signaling in genital tissue, reduced leads to Preputial epithelial morphogenesis, disrupted
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Androgen receptor antagonism leads to delayed preputial seperation via reduced fibroblast growth factor in genital-tubercle tissues | adjacent | Travis Karschnik (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | High |
| Female | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Embryo | High |
| Foetal | High |
| Fetal | High |
Key Event Relationship Description
This KER describes the mechanistic link between reduced paracrine FGF10–FGFR2‑IIIb signaling in the developing genital tubercle (KEupstream) and disruption of preputial epithelial morphogenesis (KEdownstream). FGF10 produced by genital mesenchyme signals to the epithelial FGFR2‑IIIb isoform in adjacent surface ectoderm and urethral endoderm, supporting epithelial progenitor proliferation, stratification/maturation, and the ventral outgrowth and fusion of the preputial swellings around the developing glans and urethral tube (Ohuchi et al., 2000; Petiot et al., 2005; Gredler et al., 2015; Harada et al., 2015). Reduction of this axis, whether by genetic loss of FGF10 or FGFR2‑IIIb, tissue‑specific deletion of FGFR2 in ectoderm or endoderm, or upstream pathway perturbations that lower ligand availability or receptor expression/activation (e.g., AR antagonism reducing FGFR2‑IIIb and FGF10 in GT organ culture; SHH signaling that positions mesenchymal FGF10 in GT; WNT/β‑catenin or ISL1 programs that modulate FGF10). impairs epithelial proliferation, stratification, and organization, resulting in failed ventral prepuce closure and hypospadias with ventral tethering phenotypes (Petiot et al., 2005; Gredler et al., 2015; Harada et al., 2015; Perriton et al., 2002; Haraguchi et al., 2000; Lin et al., 2008; Ching et al., 2018).
The relationship is rooted in epithelial-mesenchymal crosstalk conserved across organs: FGF10, a principal ligand for epithelial FGFR2‑IIIb, activates this receptor and its canonical cascades (ERK/AKT/PLCγ) in epithelia, providing plausible mediators between receptor output and epithelial behaviors; in GT, reduced FGFR2‑IIIb is empirically linked to reduced proliferation and disordered epithelial organization, but cascade‑level causality remains to be shown (Ohuchi et al., 2000; Itoh & Ornitz, 2011; Gredler et al., 2015). In the genital tubercle, the spatial deployment of FGF10-FGFR2‑IIIb signaling contributes to ventral prepuce expansion and closure; ectodermal FGFR2 is specifically required for ventral fusion and for maintaining a closed urethral tube, whereas endodermal FGFR2 is required for urethral epithelial maturation (Gredler et al., 2015; Harada et al., 2015; Satoh et al., 2004; Yamada et al., 2006). Within the established GT signaling network, SHH from the urethral epithelium promotes mesenchymal FGF10, and WNT/ISL1 programs influence mesenchymal FGF10 and epithelial behaviors; thus, perturbations in these inputs can secondarily diminish FGF10–FGFR2‑IIIb signaling and disrupt preputial morphogenesis. (Perriton et al., 2002; Seifert et al., 2010; Lin et al., 2008; Ching et al., 2018; Suzuki et al., 2002).
Evidence Collection Strategy
Evidence for this KER was assembled through a combination of expert knowledge and AI-assisted literature search and synthesis. Specifically, a combination of Claude (Anthropic) using Sonnet 4.6, and EPA AI, using GPT5, was used to identify, retrieve, and summarize relevant primary and secondary literature, and to draft the initial content of this KER page. All citations generated through this process were subsequently reviewed and verified by the KER author against primary sources and DOI resolution checks, prior to inclusion. Users of this KER are advised that AI-assisted evidence assembly may introduce selection bias or gaps in coverage that differ from a fully systematic human-conducted review, and independent verification of the evidence base is encouraged. A copy of the initial prompt is attached to AOP619.
A review of primary experimental literature using the following databases and search strategies was employed:
PubMed/MEDLINE and Google Scholar using the following search terms and Boolean combinations: "FGF10" AND "FGFR2" AND "prepuce" OR "preputial", "FGFR2-IIIb" AND "hypospadias" AND "genital tubercle", "FGF10 knockout" AND "external genitalia" AND "mouse", "FGFR2 conditional knockout" AND "prepuce", "FGF10 FGFR2 hypospadias human", "preputial morphogenesis" AND "fibroblast growth factor".
Searches were conducted in April 2026 with no formal date restriction. Screening criteria prioritized: (1) primary experimental studies using genetic loss-of-function models (null mutants and conditional knockouts); (2) pharmacological studies (AR antagonism) that implicate this pathway; (3) human tissue studies (immunohistochemistry, sequencing) in hypospadias patients; and (4) cross-species comparative studies. Reviews were used to triangulate but not as primary evidence sources.
Evidence Supporting this KER
Biological Plausibility
In the genital tubercle (GT), FGF10 is produced by genital mesenchyme and FGFR2‑IIIb is transcribed in adjacent surface ectoderm and urethral epithelium, positioning a paracrine axis across the mesenchyme–epithelium boundary where the preputial folds arise (Gredler et al., 2015; Satoh et al., 2004; Yamada et al., 2006; Suzuki et al., 2002). FGF10 is a major ligand for epithelial FGFR2‑IIIb across multiple organs, and high‑affinity signaling requires heparan‑sulfate proteoglycans as cofactors (Ohuchi et al., 2000; Ornitz, 2015). FGFR2b activates canonical cascades in epithelia (MAPK/ERK, PI3K/AKT, PLCγ), providing plausible mediators between receptor output and epithelial behaviors (Ornitz, 2015). In the genital tubercle, epithelial FGFR2 deletion prolongs G1, reduces proliferation, and disrupts columnar morphogenesis/adhesion and stratification, linking diminished receptor output to the epithelial behaviors required for preputial fold expansion and fusion; assignment of these effects to specific cascades in GT epithelium has not yet been shown (Gredler et al., 2015).
These pathway outputs map directly onto the epithelial behaviors needed for preputial morphogenesis. Preputial swellings elevate from the lateral GT at ~E13–E13.5 and must expand and fuse ventrally around the glans/urethral tube between ~E15.5 and E17.5 (Satoh et al., 2004; Yamada et al., 2006; Suzuki et al., 2002). When FGF10→FGFR2‑IIIb signaling is reduced, GT epithelia exhibit diminished proliferation and impaired columnar/adhesive organization, blunting lateral‑to‑ventral fold expansion and compromising midline fusion competence; consequently, the ventral prepuce fails to close, yielding ventral tethering and a persistent ventral groove by late gestation (Gredler et al., 2015; Harada et al., 2015). Genetic sufficiency data reinforce this linkage: global loss of FGFR2‑IIIb or FGF10 arrests urethral epithelial maturation and produces glans/prepuce malformations and severe hypospadias (Petiot et al., 2005). Tissue‑specific deletions show compartmental requirements, ectodermal FGFR2 is necessary for ventral prepuce closure and for maintaining a closed urethral tube, whereas endodermal FGFR2 is required for urethral epithelial proliferation, stratification, and maturation, indicating that reduced signaling in ectoderm predominantly blocks fold fusion, while reduced signaling in endoderm weakens the epithelial template on which closure depends (Gredler et al., 2015; Harada et al., 2015).
Finally, pathway context helps explain sensitivity and modifiers: SHH from the urethral epithelium promotes mesenchymal FGF10 and GT growth, and WNT/β‑catenin and ISL1 programs regulate mesenchymal FGF10 and epithelial behaviors; perturbations in these inputs can secondarily depress FGF10– FGFR2‑IIIb signaling and disrupt preputial morphogenesis (Perriton et al., 2002; Seifert et al., 2010; Lin et al., 2008; Ching et al., 2018). Because FGF10 signals via FGFR2‑IIIb and high‑affinity signaling requires heparan‑sulfate proteoglycans, disturbances in HS biosynthesis or sulfation are plausible modulators of this KER, although GT‑specific HS loss‑of‑function data were not identified (Ohuchi et al., 2000; Ornitz, 2015)
Empirical Evidence
Genetic null models (mouse)
FGFR2‑IIIb−/− and FGF10−/−. In FGFR2‑IIIb null embryos, early GT outgrowth is grossly normal, but by E13.5 the ventral urethral plate develops a precocious proximal opening and a furrow along the urethral seam; by E15.5–E17.5, the penile urethra fails to internalize and ventral prepuce does not form, yielding severe hypospadias. FGF10 null males and females similarly exhibit severe proximal hypospadias with arrested epithelial maturation. Concordant phenotypes in FGF10 and FGFR2‑IIIb nulls provide strong genetic evidence that the FGF10–FGFR2‑IIIb pair is essential for urethral tube internalization and ventral prepuce development (Petiot et al., 2005).
Tissue-specific (conditional) knockout models (mouse)
Ectoderm vs endoderm roles. Conditional deletion of FGFR2 in the surface ectoderm disrupts ventral prepuce closure and maintenance of a closed urethral tube, producing severe hypospadias and ventral tethering; mislocalization of preputial swellings is evident from the onset of prepuce development (≈E13.0) and progresses to hypospadic orifices. In contrast, endodermal FGFR2 deletion causes milder hypospadias with impaired maturation and stratification of the urethral epithelium. These data demonstrate compartment‑specific sufficiency of FGFR2 signaling for preputial epithelial morphogenesis (Gredler et al., 2015; Harada et al., 2015).
Endocrine pharmacology linking upstream perturbation to the FGF axis and downstream morphology
- Ex vivo GT organ culture: Flutamide produced a clear, dose‑dependent reduction of FGFR2‑IIIb transcripts after 48 h (10⁻⁵ M no effect; 10⁻⁴–10⁻³ M progressive loss), with co‑treatment DHT (5×10⁻⁶ M) rescuing FGFR2‑IIIb; FGF10 was also reduced at higher flutamide doses in both male and female GTs. These findings show AR‑dependent control over the FGF10–FGFR2‑IIIb axis in GT tissue (Petiot et al., 2005).
- In vivo alignment: AR antagonism during the programming window feminizes male urethral development and yields ventral tethering/failed ventral closure, consistent with the preputial defects seen with ectodermal FGFR2 loss; while in vivo FGF10/FGFR2‑IIIb transcripts were not quantified, the morphological outcomes align with reduced epithelial FGF signaling (Seifert et al., 2008; Sinclair et al., 2016). Note: Gredler’s comment on flutamide lowering FGFR2 in GT transcriptionally cites Petiot’s ex vivo data (Gredler et al., 2015; Petiot et al., 2005).
Cross-species comparative and organ culture manipulation (mouse ↔ guinea pig)
Species differences and causal tuning by FGF/SHH level. In guinea pig (which normally maintains an open urethral groove), GT expression of Shh, FGF8, FGF10, FGFR2, and Hoxd13 is >4‑fold lower than in mouse. In organ culture, Hedgehog and FGF pathway inhibitors induced/maintained a urethral groove and restrained preputial development in mouse GT, whereas recombinant SHH or FGF10 proteins promoted preputial development in guinea pig GT. These gain‑ and loss‑of‑function manipulations support that the level of FGF10–FGFR2‑IIIb (and SHH) signaling causally influences whether preputial morphogenesis proceeds versus biasing toward an open groove configuration (Wang & Zheng, 2025).
Human tissue and genetic evidence (translation; indirect)
- Protein-level alterations in prepuce/foreskin. In hypospadiac foreskin, immunohistochemistry demonstrates altered or reduced staining for FGF10/FGFR2 relative to controls (with some studies including FGF8); some cohorts report significant protein differences without concordant mRNA changes by qPCR, suggesting post‑transcriptional regulation or altered localization (Haid et al., 2020; Emaratpardaz et al., 2024).
- Severity correlation. In preputial tissue from boys with hypospadias, reduced FGF10 protein levels (IHC/Western) have been reported, with greater reduction in more severe cases, supporting a link between diminished upstream FGF10 and preputial pathology (Yamada et al., 2025).
- Genetic associations. Rare FGFR2 variants have been identified in familial hypospadias (Swedish cohort), and population‑level FGF10 SNPs are associated with increased hypospadias risk in a large, diverse cohort, supporting human plausibility that perturbations of the FGF10–FGFR2‑IIIb axis can contribute to preputial/urethral developmental defects (Beleza‑Meireles et al., 2007; Carmichael et al., 2013). For anatomical translation of epithelial compartments to human foreskin/prepuce, see keratin boundary mapping in fetal tissues (Kurzrock et al., 1999).
Uncertainties and Inconsistencies
Human protein vs mRNA discordance and postnatal sampling
In hypospadiac foreskin, immunohistochemistry shows altered/lower FGF8, FGF10, and FGFR2 protein patterns versus controls (p < 0.01), yet qPCR detects no significant mRNA differences in the same samples; cases were postnatal surgical specimens (mean age ≈25 months for patients, ≈77 months for controls), not embryonic tissues. This limits inference about whether reduced prenatal FGF10/FGFR2‑IIIb signaling is causal versus secondary to altered tissue architecture or post‑transcriptional regulation (Haid et al., 2020). A separate pediatric foreskin study also reports lower FGF8/FGF10/FGFR2 IHC signals in hypospadias (p < 0.05), further supporting protein‑level differences with uncertain transcriptional basis (Emaratpardaz et al., 2024).
Quantitative response–response gap in vivo
Ex vivo GT culture shows a clear dose‑response for transcript loss after 48 h of AR antagonism (FGFR2‑IIIb, and FGF10 at higher doses), and compartmental sufficiency is defined genetically. However, graded in vivo measurements linking partial reductions in FGF10/FGFR2‑IIIb signaling to incremental failures of ventral prepuce closure are limited (semi‑quantitative rather than absolute readouts of receptor signaling; few time‑resolved, compartment‑specific quantifications) (Petiot et al., 2005; Gredler et al., 2015).
Cross‑species endpoint definition
Because guinea pig normally retains an open urethral groove and lacks full ventral prepuce enclosure, “disrupted preputial epithelial morphogenesis” should be scored as shifts in prepuce‑vs‑groove balance in that species. Applying a mouse‑style “failed ventral enclosure” endpoint across species could misclassify outcomes and obscure true cross‑species concordance (Wang & Zheng, 2025).
Known modulating factors
|
Modulating Factor |
Details |
Effect on KER |
References |
|
Heparan sulfate proteoglycans (HSPGs) |
HSPGs are required cofactors that promote high‑affinity FGF10–FGFR2‑IIIb complex formation and signaling; HS chain length and sulfation pattern modulate ligand–receptor binding and signaling strength. |
Disruption of HS biosynthesis/sulfation is expected to attenuate FGF10–FGFR2‑IIIb signaling and weaken preputial epithelial morphogenesis; GT‑specific HS loss‑of‑function data are not yet available. |
Ohuchi et al., 2000; Ornitz, 2015. |
|
Sex (androgen environment) |
Male and female GT explants show similar dose‑dependent reductions of FGFR2‑IIIb and FGF10 with flutamide ex vivo, but in vivo AR antagonism during the window feminizes male urethral development while females are largely unaffected. |
The molecular AR→FGF axis operates in both sexes, but reduced signaling has greater morphogenetic consequences in males. |
Petiot et al., 2005; Seifert et al., 2008; Sharpe, 2020. |
|
Sonic hedgehog (SHH) pathway activity |
SHH from the urethral epithelium promotes mesenchymal FGF10 and GT growth; conditional Shh loss reduces FGF10 (GT), and SHH/FGF manipulations in organ culture shift the balance between preputial outgrowth and persistence of a urethral groove. Shh does not appear to regulate FGFR2 transcription in GT. |
Reduced SHH can secondarily lower FGF10 and diminish the upstream KE, biasing development toward groove persistence and restrained preputial development. |
Perriton et al., 2002; Seifert et al., 2010; Gredler et al., 2015; Wang & Zheng, 2025. |
|
WNT/β‑catenin signaling |
β‑catenin is required in external genital epithelial tissues; WNT programs interface with epithelial adhesion/morphogenesis and with mesenchymal cues that include FGF10. |
Reduced WNT/β‑catenin signaling can impair epithelial behaviors needed for preputial fusion and may lower FGF10 support, weakening the upstream KE and exacerbating KEdownstream defects. |
Lin et al., 2008. |
|
ISL1 transcriptional program |
ISL1 controls mesenchymal expansion via regulation of Bmp4, FGF10, and Wnt5a in the developing external genitalia. |
Reduced ISL1 activity diminishes FGF10 and related cues, decreasing FGF10–FGFR2‑IIIb signaling and compromising preputial epithelial morphogenesis. |
Ching et al., 2018. |
|
Ligand redundancy at FGFR2‑IIIb |
FGFR2‑IIIb can bind multiple epithelial ligands (e.g., FGF7, FGF10); FGF10 is a major ligand across epithelia. |
Partial compensation by other ligands (e.g., FGF7) could blunt the impact of reduced FGF10 on this KER, potentially modifying effect size and penetrance. |
Ohuchi et al., 2000; Itoh & Ornitz, 2011. |
|
FGFR2 compartment specificity |
Ectodermal FGFR2 is required for ventral prepuce closure and maintenance of a closed urethral tube; endodermal FGFR2 supports urethral epithelial proliferation/stratification. |
The same reduction in upstream signaling produces different downstream severities depending on which epithelial compartment is most affected. |
Gredler et al., 2015; Harada et al., 2015. |
Quantitative Understanding of the Linkage
Response-response Relationship
Direct, quantitative dose–response data that map graded reductions in FGF10/FGFR2‑IIIb signaling to graded severity of preputial epithelial morphogenesis defects remain limited. However, several semi‑quantitative relationships support a graded or threshold‑like linkage:
Genetic dosage and compartment specificity (mouse). Homozygous loss of FGFR2‑IIIb (or FGF10) produces severe hypospadias with failure of ventral prepuce formation, whereas early GT outgrowth remains grossly normal, indicating a threshold requirement for epithelial FGFR2‑IIIb signaling during the period of preputial outgrowth/fusion (Petiot et al., 2005). Conditional deletions show graded, compartment‑specific consequences: endodermal FGFR2 loss yields milder hypospadias with impaired epithelial maturation, while ectodermal FGFR2 loss causes severe failure of ventral prepuce closure and ventral tethering, implying that the magnitude and site of receptor loss scale with the severity of preputial defects (Gredler et al., 2015; Harada et al., 2015).
Temporal and morphometric context (mouse). The period of preputial elevation and ventral fusion (~E13–E17.5) aligns with the stages when epithelial FGFR2‑IIIb signaling is required; failure of ventral prepuce closure becomes apparent as development proceeds toward late gestation, consistent with a progressive deficit when upstream signaling is reduced (Satoh et al., 2004; Yamada et al., 2006; Suzuki et al., 2002; Gredler et al., 2015; Harada et al., 2015).
Together, these findings support a semi‑quantitative picture in which partial attenuation of FGF10/FGFR2‑IIIb signaling can produce milder epithelial maturation defects, while more profound or compartment‑targeted reductions (especially in ectoderm) cross a threshold that results in failed ventral prepuce closure and ventral tethering. Nonetheless, the field lacks in vivo, compartment‑resolved measurements that link incremental decreases in ligand/receptor levels or receptor activation (e.g., pERK readouts) to graded preputial outcomes.
Time-scale
The temporal relationship is clear from mouse developmental staging. FGFR2‑IIIb transcripts are detected in the urethral plate epithelium beginning at E10.5 and persist through E16.5; expression appears in the paired preputial swellings as they emerge along the lateral edges of the tubercle at ~E13.5 (Petiot et al., 2005). Consistent with this, FGF signaling is first detected in GT mesenchyme at ~E11.5, is evident in mesenchyme, ectoderm, and endoderm by ~E13.5, and becomes predominantly epithelial by ~E14.5 (Harada et al., 2015). The preputial swellings initiate around E13.0–E13.5 and then grow laterally and ventrally to form the prepuce; by E15.5 the swellings cover the proximal glans, and by ~E17.0–E17.5 the prepuce normally surrounds the glans and penile shaft (Satoh et al., 2004; Suzuki et al., 2002; Petiot et al., 2005; Gredler et al., 2015; Wang & Zheng, 2025). In FGFR2‑IIIb null embryos, ventral defects in the urethral plate and preputial domain are evident by E13.5, and the ventral prepuce fails to form thereafter; by late gestation the urethra remains open with only lateral preputial tissue present (Petiot et al., 2005). In ectoderm‑specific FGFR2 deletion, mislocalization of the preputial swellings is already apparent at ~E13.0 and progresses to failed ventral prepuce closure (Gredler et al., 2015). Taken together, these data indicate that detectable disruption of preputial morphogenesis follows within roughly one to two embryonic days of the stage when preputial swellings normally initiate (~E13.0–E13.5), with the full morphogenetic outcome (failed ventral enclosure/ventral tethering) established over the ensuing embryonic days through ~E17.0–E17.5 (Petiot et al., 2005; Gredler et al., 2015).
Known Feedforward/Feedback loops influencing this KER
SHH→FGF10 feed‑forward influence
Evidence: In the genital tubercle (GT), SHH is produced by the urethral epithelium and promotes mesenchymal growth; Shh loss reduces mesenchymal FGF10 in GT, placing SHH upstream of the FGF10–FGFR2‑IIIb axis (Perriton et al., 2002; Seifert et al., 2010). In organ culture, inhibiting SHH/FGF signaling restrains preputial development and maintains a urethral groove in mouse GT, whereas adding SHH or FGF10 promotes preputial outgrowth in guinea pig GT, which normally exhibits an open groove (Wang & Zheng, 2025). Together, these findings support a feed‑forward influence in which SHH maintains/boosts FGF10 to drive epithelial FGFR2‑IIIb signaling needed for preputial morphogenesis.
FGF→SHH feedback in GT (not demonstrated)
Evidence: In limb, FGFR2‑IIIb acts upstream of Shh, illustrating a reciprocal logic in another organ (Revest et al., 2001). In GT, however, data argue against a similar feedback: conditional Shh deletion did not alter FGFR2 mRNA in GT, and early urethral Shh/FGF8 domains are established even in FGFR2‑IIIb nulls (though maturation subsequently fails), indicating that direct FGF→Shh feedback has not been shown in GT (Gredler et al., 2015; Petiot et al., 2005). Thus, a reciprocal SHH↔FGF loop (as in lung branching) is not established for genital preputial morphogenesis.
SHH/FGF cooperation vs formal feedback loop
Evidence: The combined gain‑ and loss‑of‑function organ culture data indicate that SHH and FGF10 act cooperatively to bias development toward preputial outgrowth versus a persistent urethral groove (Wang & Zheng, 2025). Whether this cooperation constitutes a bona fide feedback loop (with mutual regulation) or parallel, convergent inputs remains unresolved for GT.
Domain of Applicability
Taxonimic Applicability:
In Mus musculus, global loss of FGF10 or FGFR2‑IIIb and tissue‑specific deletion of FGFR2 demonstrate that epithelial FGFR2‑IIIb signaling is required for urethral epithelial proliferation/stratification and ventral prepuce closure, with ectodermal deletion yielding severe failure of ventral enclosure and ventral tethering (Petiot et al., 2005; Gredler et al., 2015; Harada et al., 2015). In Rattus norvegicus, anti‑androgen exposures within the masculinization programming window (GD15.5–18.5) feminize urethral development and produce ventral fusion/prepuce defects, consistent with downstream consequences of reduced epithelial FGF signaling, although direct compartment‑specific FGFR2‑IIIb genetics in rat are limited (Welsh et al., 2008; Seifert et al., 2008; Sinclair et al., 2016; Sharpe, 2020). In Cavia porcellus, which normally retains an open urethral groove, organ‑culture manipulations show that inhibiting SHH/FGF restrains prepuce and maintains a groove in mouse GT, whereas adding SHH or FGF10 promotes prepuce outgrowth in guinea pig GT, indicating that the level of FGF10– FGFR2‑IIIb signaling causally biases development toward prepuce formation versus groove persistence, albeit with limited in vivo genetic confirmation in this species (Wang & Zheng, 2025). Together, these data provide a strong rodent‑wide rationale that reduced FGF10–FGFR2‑IIIb signaling in genital tissues leads to disrupted preputial epithelial morphogenesis.
Human foreskin from boys with hypospadias shows altered protein‑level patterns for FGF10/FGFR2 (and FGF8) versus controls; cohort genetics implicate FGF10 SNPs (population‑level risk) and rare FGFR2 variants (familial cases). Direct mechanistic data in embryonic human GT during the sensitive window are not available, so support is correlative.
Mammalia is plausible given conserved mesenchyme‑to‑epithelium FGF10→FGFR2‑IIIb signaling in external genital development, with caveats for species‑specific distal urethral/prepuce anatomy and timing (Amato et al., 2022; Haraguchi et al., 2000; Perriton et al., 2002; Seifert et al., 2010; Sharpe, 2020).
Life Stage Applicability:
In mouse, FGFR2‑IIIb is detectable in the urethral plate by ~E10.5, but preputial swellings initiate at ~E13–E13.5, cover the proximal glans by ~E15.5, and normally enclose the glans/shaft by ~E17–E17.5; loss of epithelial FGFR2 signaling produces defects detectable at or soon after preputial initiation and culminates in failed ventral prepuce closure by late gestation (Petiot et al., 2005; Satoh et al., 2004; Suzuki et al., 2002; Yamada et al., 2006; Gredler et al., 2015; Harada et al., 2015). In rat, sensitivity is concentrated within the fetal masculinization programming window (GD15.5–18.5), during which upstream anti‑androgen exposure yields ventral fusion/prepuce defects consistent with reduced epithelial FGF signaling (Welsh et al., 2008; Seifert et al., 2008; Sharpe, 2020). By analogy, the presumptive human window is ~8–14 gestational weeks, though direct fetal mechanistic data are limited (Sharpe, 2020). In guinea pig, organ‑culture experiments show that modulating SHH/FGF levels during embryonic stages shifts development toward preputial outgrowth versus persistent urethral groove, underscoring a level‑ and time‑dependent requirement for FGF10–FGFR2‑IIIb during the species‑specific embryonic window (Wang & Zheng, 2025).
Sex Applicability:
This KER operates in both sexes during the sexually indifferent stage of external genital development: in GT organ culture, AR antagonism produces similar dose‑dependent reductions of FGFR2‑IIIb and FGF10 in male and female explants, and DHT rescues FGFR2‑IIIb, indicating AR‑dependent control of the FGF10–FGFR2‑IIIb axis in both sexes (Petiot et al., 2005). Global loss of FGFR2‑IIIb or FGF10 yields severe external genital malformations consistent with hypospadias in embryos, with Petiot reporting effects across sexes, while tissue‑specific deletions of FGFR2 (characterized primarily in males) show that ectodermal FGFR2 is required for ventral prepuce closure and endodermal FGFR2 for urethral epithelial maturation (Petiot et al., 2005; Gredler et al., 2015). In vivo, however, androgen suppression within the programming window feminizes male urethral development whereas flutamide‑treated females show little change in urethral position, indicating that downstream morphogenetic consequences are more pronounced in males; this male‑biased sensitivity is consistent with higher androgen tone during the window rather than proven sex‑biased amplification of FGF10/FGFR2 expression per se (Seifert et al., 2008; Sharpe, 2020).
References
Amato, R., Yao, H.-H.-C., & Zhao, F. (2022). One tool for many jobs: Divergent and conserved actions of androgen signaling in male internal reproductive tract and external genitalia. Frontiers in Endocrinology, 13, 910964. https://doi.org/10.3389/fendo.2022.910964
Beleza-Meireles, A., Lundberg, F., Lagerstedt, K., et al. (2007). FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. European Journal of Human Genetics, 15(4), 405–410. https://doi.org/10.1038/sj.ejhg.5201777
Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., & Shaw, G. M. (2013). Hypospadias and genes related to genital tubercle and early urethral development. Journal of Urology, 190(5), 1884–1892. https://doi.org/10.1016/j.juro.2013.05.061
Ching, S. T., Infante, C. R., Du, W., Sharir, A., Park, S., Menke, D. B., & Klein, O. D. (2018). Isl1 mediates mesenchymal expansion in the developing external genitalia via regulation of Bmp4, Fgf10 and Wnt5a. Human Molecular Genetics, 27(1), 107–119. https://doi.org/10.1093/hmg/ddx388
Emaratpardaz, N., Turkyilmaz, Z., et al. (2024). Comparison of FGF-8, FGF-10, FGF-Receptor 2, androgen receptor, estrogen receptor-α and SS in healthy and hypospadiac children. Balkan Journal of Medical Genetics, 27(1), 21–29. https://doi.org/10.2478/bjmg-2024-0002
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. https://doi.org/10.1242/dev.119891
Haid, B., Pechriggl, E., Nägele, F., et al. (2020). FGF8, FGF10 and FGF receptor 2 in foreskin of children with hypospadias: An analysis of immunohistochemical expression patterns and gene transcription. Journal of Pediatric Urology, 16(1), 41.e1–41.e10. https://doi.org/10.1016/j.jpurol.2019.10.007
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. https://doi.org/10.1002/dvdy.24277
Haraguchi, R., Suzuki, K., Murakami, R., et al. (2000). Molecular analysis of external genitalia formation: The role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development, 127(11), 2471–2479.
Itoh, N., & Ornitz, D. M. (2011). Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease. Journal of Biochemistry, 149(2), 121–130. https://doi.org/10.1093/jb/mvq166
Kurzrock, E. A., Baskin, L. S., & Cunha, G. R. (1999). Ontogeny of the male urethra: Theory of endodermal differentiation. Differentiation, 64(2), 115–122.
Lin, C., Yin, Y., Long, F., & Ma, L. (2008). Tissue-specific requirements of β-catenin in external genitalia development. Development, 135(16), 2815–2825. https://doi.org/10.1242/dev.020586
Ohuchi, H., Hori, Y., Yamasaki, M., Harada, H, Sekine, K., Kato, S., & Itoh, N. (2000). FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochemical and Biophysical Research Communications, 277(3), 643–649. https://doi.org/10.1006/bbrc.2000.3721
Ornitz, D. M. (2015). The fibroblast growth factor signaling pathway. WIREs Developmental Biology, 4(3), 215–266. https://doi.org/10.1002/wdev.176
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