title: Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia.
abstract: In humans and mice, mutations in Hoxa13 cause malformation of limb and genitourinary (GU) regions. In males, one of the most common GU malformations associated with loss of Hoxa13 function is hypospadia, a condition defined by the poor growth and closure of the urethra and glans penis. By examining early signaling in the developing mouse genital tubercle, we show that Hoxa13 is essential for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium. In Hoxa13(GFP)-mutant mice, hypospadias occur as a result of the combined loss of Fgf8 and Bmp7 expression in the urethral plate epithelium, as well as the ectopic expression of noggin (Nog) in the flanking mesenchyme. In vitro supplementation with Fgf8 restored proliferation in homozygous mutants to wild-type levels, suggesting that Fgf8 is sufficient to direct early proliferation of the developing genital tubercle. However, the closure defects of the distal urethra and glans can be attributed to a loss of apoptosis in the urethra, which is consistent with reduced Bmp7 expression in this region. Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling. Finally, a novel role for Hoxa13 in the vascularization of the glans penis is also identified.
authors.affiliation: Shriners Hospital for Children, Portland, OR 97239, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Morgan
authors.forename: Susan B
authors.initials: SB
authors.lastname: Nguyen
authors.forename: Virginia
authors.initials: V
authors.lastname: Scott
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
mesh_terms: D000818:Animals; D017209:Apoptosis; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation; D010413:Penis / Q000196:embryology; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C496456:FGF8 protein, human; C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016212:Transforming Growth Factor beta; C099959:homeobox protein HOXA13; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D012313:RNA