Adult Gli2+/-;Gli3Δ699/+ Male and Female Mice Display a Spectrum of Genital Malformation.
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.
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Fei
F
He
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Pedram
P
Akbari
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Rong
R
Mo
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Jennifer J
JJ
Zhang
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Chi-Chung
CC
Hui
Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, Washington, DC, United States of America.
Peter C
PC
Kim
Program in Developmental & Stem Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Urology, Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Walid A
WA
Farhat
D001003:Anal Canal / Q000002:abnormalities; D000818:Animals; D003456:Cryptorchidism / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007021:Hypospadias / Q000235:genetics / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010413:Penis / Q000002:abnormalities; D014564:Urogenital Abnormalities / Q000235:genetics* / Q000503:physiopathology*; D014599:Uterus / Q000002:abnormalities* / Q000503:physiopathology; D014621:Vagina / Q000002:abnormalities; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3