• PMID: 27814383
• Gene Name: GLI2
• Condition: Disorders of sexual development (DSD), Cryptorchidism, Hypospadias, incomplete fusion of the scrotal sac
• Association: Associated
• Mutation: Gli2+/-
• Sex: Male
• Infertility type: Male infertility

Adult Gli2+/-;Gli3?699/+ Male and Female Mice Display a Spectrum of Genital Malformation

He F, Akbari P, Mo R, Zhang JJ, Hui CC, Kim PC, Farhat WA.

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. FAU - He, Fei AU - He F AD - Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Akbari, Pedram AU - Akbari P AD - Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Mo, Rong AU - Mo R AD - Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Zhang, Jennifer J AU - Zhang JJ AD - Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Hui, Chi-Chung AU - Hui CC AD - Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. AD - Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. FAU - Kim, Peter C AU - Kim PC AD - Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, DC, United States of America.