Tissue-specific requirements of -catenin in external genitalia development

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 -catenin plays indispensable and distinct roles in each of the aforementioned three tissue layers in early androgen-independent GT development. WNT--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, -catenin is required in the mesenchyme to promote cell proliferation. By contrast, -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 -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.