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 Hoxa13GFP-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.

Hypospadias: Interactions between environment and genetics

“…in the development of the phallus since knock-out of these genes in mice induces a malformation in the external genitalia consistent with hypospadias [23]. In humans, the hand-foot-genital syndrome (HFGS) [24,25] …”

Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling

“…The phenotypes of gene knockout mice have revealed that several growth and signaling factor families play fundamental roles in reproductive and urogenital organ formation (Batourina et al, 2002;Doles et al, 2006;Haraguchi et al, 2001;Haraguchi et al, 2000;Huang et al, 2005;Jamin et al, 2002;Kobayashi and Behringer, 2003;Kondo et al, 1996;McMahon et al, 2003;Morgan et al, 2003;Perriton et al, 2002;Suzuki et al, 2003). Shh is expressed in the cloacal epithelia and is vital for the regulation of structures derived from the genital tubercle (GT) and the urogenital sinus, such as the external genitalia and the prostate, respectively (de Santa Barbara and Roberts, 2002;Freestone et al, 2003;Pu et al, 2004).…”

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

“…This is particularly true of 5Ј HoxA and HoxD genes, which are involved in limb patterning (reviewed in references 49 and 65). The inactivation of the Hoxd13 gene in mice, for instance, causes a phenotype resulting from defects in the proliferation and/or condensation of limb mesenchymal cells (11,14).Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins.…”

“…Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins.…”