Adult Gli2+/-;Gli3Δ699/+ Male and Female Mice Display a Spectrum of Genital Malformation.

Fei He,Walid A Farhat,Rong Mo,Pedram Akbari,Chi-Chung Hui,Peter C Kim,Jennifer J Zhang,Wei Yan

doi:10.1371/journal.pone.0165958

Fei He, Walid A Farhat + Show 6 more

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https://doi.org/10.1371/journal.pone.0165958

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Abstract

Disorders of sexual development (DSD) encompass a broad spectrum of urogenital malformations and are amongst the most common congenital birth defects. Although key genetic factors such as the hedgehog (Hh) family have been identified, a unifying postnatally viable model displaying the spectrum of male and female urogenital malformations has not yet been reported. Since human cases are diagnosed and treated at various stages postnatally, equivalent mouse models enabling analysis at similar stages are of significant interest. Additionally, all non-Hh based genetic models investigating DSD display normal females, leaving female urogenital development largely unknown. Here, we generated compound mutant mice, Gli2+/–;Gli3Δ699/+, which exhibit a spectrum of urogenital malformations in both males and females upon birth, and also carried them well into adulthood. Analysis of embryonic day (E)18.5 and adult mice revealed shortened anogenital distance (AGD), open ventral urethral groove, incomplete fusion of scrotal sac, abnormal penile size and structure, and incomplete testicular descent with hypoplasia in male mice, whereas female mutant mice displayed reduced AGD, urinary incontinence, and a number of uterine anomalies such as vaginal duplication. Male and female fertility was also investigated via breeding cages, and it was identified that male mice were infertile while females were unable to deliver despite becoming impregnated. We propose that Gli2+/–;Gli3Δ699/+ mice can serve as a genetic mouse model for common DSD such as cryptorchidism, hypospadias, and incomplete fusion of the scrotal sac in males, and a spectrum of uterine and vaginal abnormalities along with urinary incontinence in females, which could prove essential in revealing new insights into their equivalent diseases in humans.

Highlights

Disorders of sexual development (DSD) are among the most common human birth defects, affecting nearly 3% of all newborns [1]
Hh signaling has been identified as a key regulator of processes that are vital to proper genital development such as genital tubercle (GT) outgrowth and patterning, onset of sexual differentiation, and cloacal septation [8, 16]
While drastic reduction or complete inactivation of the Hh pathway leads to severe hindgut malformations and embryonic lethality, moderate reduction of Hh pathway activity results in viable mice with urogenital malformations and compromised sexual differentiation

Summary

Introduction

Disorders of sexual development (DSD) are among the most common human birth defects, affecting nearly 3% of all newborns [1]. This high incidence rate can be attributed to the complex set of developmental events that need to be harmoniously synchronized from the onset of sexual differentiation until the emergence of sexually functional adult [2]. The early and severe genital and cloacal phenotypes of Shh null mice and the sex specific phenotypes of Dhh null mice have limited the generation of a viable mouse model for common DSD affecting both male and females

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