# Dissecting the Genetic and Cellular Mechanisms of Urethral Tube Defects

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $331,315

## Abstract

PROJECT SUMMARY/ABSTRACT
 Malformations of the lower genitourinary tract are among the most common birth defects in humans.
Hypospadias -- a malformation of the external genitalia characterized by failure of urethral tube closure and
incomplete formation of the prepuce (foreskin) and ventral penis -- affects an estimated 1 of every 250 live
births. Affected children can have oversized or multiple urethral openings, and those with severe hypospadias
are born with ambiguous genitalia. All but the mildest forms require surgical intervention. The etiology of
hypospadias is not understood, but recent discoveries of copy number variations (CNVs) in affected individuals
suggest a genetic basis for increased susceptibility to hypospadias, which may be compounded by exposure to
environmental endocrine disrupting chemicals (EDCs). Our limited knowledge of the most basic molecular
mechanisms that pattern the genital tubercle has been an obstacle to understanding how the urethral tube
forms during normal development, how hypospadias arises, and how EDCs can affect the gene regulatory
networks (GRNs) that orchestrate external genital development. Our group previously showed that deletion of
Fibroblast growth factor receptor-2 (Fgfr2) causes hypospadias in mice, and recent studies have illustrated
the translational importance of this discovery by identifying deletions affecting the FGFR2 locus in boys with
urethral tube defects. In this project, we aim to identify the mechanisms by which Fgfr2 orchestrates urethral
tube formation. The goal of Specific Aim 1 is to understand the genetic control of urethra development by
dissecting the Fgfr2 GRN to identify downstream targets and to elucidate their functions. The goal of Specific
Aim 2 is to understand how Fgfr2 regulates the cellular processes that drive urethral tubulogenesis. These
objectives will be accomplished by integrating developmental genetics, cell biology, and novel transgenic
mouse models. An immediate translational impact will come through direct comparison of the mouse data to
human cases of hypospadias with known CNVs, which will establish the mechanistic links between mutant
genotypes and the phenotypes of boys with structural defects of the urethra.

## Key facts

- **NIH application ID:** 9964793
- **Project number:** 5R01DK110408-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** MARTIN J COHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,315
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964793

## Citation

> US National Institutes of Health, RePORTER application 9964793, Dissecting the Genetic and Cellular Mechanisms of Urethral Tube Defects (5R01DK110408-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964793. Licensed CC0.

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