# Visualizing and elucidating the FGF-dependent mechanisms of urethral morphogenesis

> **NIH NIH F32** · UNIVERSITY OF FLORIDA · 2020 · $65,310

## Abstract

PROJECT SUMMARY
 Hypospadias is a birth defect wherein the urethral opening is displaced from the distal end of the penis
and instead terminates on the ventral side of the penis, or in severe cases, on the scrotum or perineum.
Hypospadias is one of the most common birth defects, affecting approximately 1 in 125 live male births.
Surgery is currently the only treatment, which comes with a risk of complications and recurrence. Recent work
has demonstrated that both genetic factors and environmental factors such as embryonic exposure to
endocrine disrupting chemicals can increase the rate of hypospadias. Despite these studies, we still do not
have a good grasp on what aspects of genitalia morphogenesis become disrupted and result in hypospadias.
 The embryonic genital tubercle (GT) gives rise to either the penis or clitoris, and contains tissues from
all three germ layers. The endodermal component of the GT primarily gives rise to the urethra, mesodermal
cells contribute to supportive structures within the external genitalia, and the ectoderm gives rise to the
overlying skin. During GT development, the endoderm and ectoderm are connected at an endoderm/ectoderm
junction (EEJ) on the ventral side of the GT, forming one of very few sites in the body where such a junction
occurs. This junction is remodeled away over the course of penis development and urethral internalization,
leading to distal positioning of the urethral meatus; the EEJ remains intact during and after clitoral
development, resulting in the ventral position of the urethral opening between the clitoris and vagina. This
leads to the hypothesis that EEJ remodeling is necessary for urethral internalization in the penis, and
disruptions to the EEJ cause hypospadias. To test this hypothesis, this proposal uses mouse mutants in the
Fgf signaling pathway as a model to test how disruptions of the EEJ result in GT malformations: mice with
Fgfr2 mutations display endodermal and ectodermal defects in the GT and subsequently develop severe
hypospadias. Aim 1 of this proposal will test how Fgfr2 regulates cell movements at the EEJ during urethral
internalization; this aim makes use of a novel GT organ culture system coupled with four-dimensional live
imaging techniques to directly visualize morphogenesis of the mouse EEJ. Aim 2 will examine the
biomechanical mechanisms underlying urethral internalization and test the role of extracellular matrix adhesion
in contributing to EEJ development.
 The findings from this proposal will generate an atlas of the cell and tissue movements which occur
during urethral formation in the mouse, a resource which is not available for most mammalian organ systems.
The research proposed here will not only shine a light onto the morphogenetic mechanisms underlying normal
external genitalia development, but will also provide insight into how hypospadias arise and will help shape
potential preventative measures for this common congenital defect.

## Key facts

- **NIH application ID:** 10154922
- **Project number:** 1F32DK127867-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Chase Dallas Bryan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154922

## Citation

> US National Institutes of Health, RePORTER application 10154922, Visualizing and elucidating the FGF-dependent mechanisms of urethral morphogenesis (1F32DK127867-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10154922. Licensed CC0.

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