Tissue-specific requirements of β-catenin in external genitalia development

Abstract

External genitalia are body appendages specialized for internal fertilization. Their development can be divided into two phases, an early androgen-independent phase and a late androgen-dependent sexual differentiation phase. In the early phase, the embryonic anlage of external genitalia, the genital tubercle (GT), is morphologically identical in both sexes. Although congenital external genitalia malformations represent the second most common birth defect in humans, the genetic pathways governing early external genitalia development and urethra formation are poorly understood. Proper development of the GT requires coordinated outgrowth of the mesodermally derived mesenchyme and extension of the endodermal urethra within an ectodermal epithelial capsule. Here, we demonstrate that β-catenin plays indispensable and distinct roles in each of the aforementioned three tissue layers in early androgen-independent GT development. WNT-β-catenin signaling is required in the endodermal urethra to activate and maintain Fgf8 expression and direct GT outgrowth, as well as to maintain homeostasis of the urethra. Moreover, β-catenin is required in the mesenchyme to promote cell proliferation. By contrast, β-catenin is required in the ectoderm to maintain tissue integrity, possibly through cell-cell adhesion during GT outgrowth. The fact that both endodermal and ectodermal β-catenin knockout animals develop severe hypospadias in both sexes raises the possibility that the deregulation of any of these functions can contribute to the etiology of congenital external genital defects in humans.

Functional and phylogenetic analysis shows thatFgf8is a marker of genital induction in mammals but is not required for external genital development

“…4B), indicating that Fgf8 is not required for the expression of Bmp4, Wnt5a, Hoxd13 or Shh in the genital tubercle. These findings are consistent with the recent report that removal of β-catenin in the cloacal endoderm results in the loss of Fgf8 expression, but Hoxa13, Hoxd13, Msx2 and Wnt5a expression remains unaffected in the genital tubercle (Lin et al, 2008). …”

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

“…Although the incidence of hypospadias is increasing, its etiology remains unknown. Several genes are suggested as the candidate genes for the urethral formation based on analyses of knockout mice (10,(29)(30)(31)(32)(33) that Mafb is a pivotal mediator of androgen actions during embryonic urethral masculinization. Another characteristic of the masculinization of external genitalia is the difference in the GT organ size.…”

“…Genedriven GT outgrowth regulated by several growth factors has been proposed as essential for androgen-independent early embryonic GT growth. Genetic analyses based on several KO mouse models indicate that the failure of such early growth leads to abnormal size of the GT in either sex (31,37,38). In addition to such early organ size control, several growth factor signals can modulate embryonic masculinization of the size of the GT (3, 7).…”

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

“…Based on the discovery that androgen and estrogen control sexual differentiation of external genitalia by regulating urethral epithelial apoptosis in the embryo and mesenchymal cell proliferation in the neonate and the observation that male and female genitalia show differences in AR and ERα activity at these two stages, we tested the hypothesis that the gene network controlling early genital development may become differentially regulated in males and females during sexual differentiation. Given that the Hedgehog, bone morphogenetic protein (Bmp), Wnt, and fibroblast growth factor (Fgf) signaling pathways play key roles in genital development and that mutations of genes in these pathways result in malformations of external genitalia (13,(35)(36)(37)(38)(39)(40)(41), we tested whether AR or ERα signaling regulates the expression levels of genes in these pathways. Quantification of the transcript levels of 88 genes in males treated with flutamide and in control males at E15.5 identified 22 genes with significant responses to flutamide (Fig.…”