That the early development of vertebrate external genitalia resembles that of vertebrate limbs is a little known fact — but then this aspect of vertebrate development is rarely the focus of research. It was previously shown that fragments of the developing genital region harbour a signalling activity akin to the zone of polarizing activity in the vertebrate limb. These findings are now extended by Perriton and colleagues, who show that external genitalia are patterned by signals that emanate specifically from the urethral epithelium and that Sonic hedgehog (Shh) has a key role in genital development.

Previous work that highlighted the developmental similarity between limbs and external genitalia implicated the genital tubercle — the region that gives rise to the penis and clitoris — as a source of mild polarizing activity. But because the grafts contained the urethral epithelium and the genital mesenchyme it was unclear which tissue provided the signal. When Perriton et al. grafted each tissue separately onto chick limb buds they saw mirror-image duplication of digits — a hallmark of polarizing activity — but only in the case of the urethral epithelium, proving that this was the true source of the patterning signals. Additionally, some morphological features of the induced limb suggested that the urethral epithelium can drive tissue movements that are characteristic of genital morphogenesis.

So, what is the molecular basis of this signal? Out of 30 genes involved in limb development, 26 were also expressed in the genital tubercle, further supporting the existence of a common developmental mechanism. The authors focused on one of the two signalling molecules that were expressed in the developing urethra — Shh — and found that, although the outgrowth of the genital region was initiated, it wasn't maintained in Shh−/− mouse embryos. The expression of Fgf8 , Bmp4 , Wnt5a and Fgf10 — genes that, together with Shh, pattern the vertebrate limb — was either downregulated or not detectable in the external genitalia of Shh−/− mice. The authors also showed that excessive apoptosis contributes to a lack of the genital outgrowth in Shh−/− mice.

These results implicate Shh as the main urethral signal that is essential for external genital development. The authors showed that genital development is not maintained in the absence of Shh because normal patterning and growth fail. These findings substantially extend our understanding of genital development. The hope is that they will encourage more research into this often-neglected area of development.