External genitalia (the penis and the clitoris) develop from an embryonic primordium called the genital tubercle (GT), the development of which, like that of the limb bud, involves epithelial-mesenchymal interactions and the coordinated function of multiple signalling cascades. In this issue, three papers provide new information about the involvement of sonic hedgehog (Shh) in GT development in mice.
On p. , Lin et al. describe the function of Shh during early GT development. By removing Shh at different stages of development, they show that Shh is required continuously during GT initiation and subsequent androgen-independent GT growth. By removing the Shh signal transducer smoothened in different tissue layers, they show that the GT mesenchyme is a target of Shh signalling. Finally, they show that Shh exerts its function in part by maintaining the GT signalling centre, the distal urethral epithelium (DUE), but also reveal that both DUE-dependent and -independent events occur downstream of Shh during GT development.
On p. , Miyagawa et al. describe a novel signalling cascade that controls GT formation. By analysing Gli mutant mice, they show that the dosage of the Shh signal affects GT development and modulates the level of Wnt/β-catenin activity. This activity plays a key role in the formation of the GT by inducing multiple growth factors. However, note the researchers, both Fgf8 and Fgf4 are dispensable for GT outgrowth. Other data suggest that Wnt/β-catenin signalling in the DUE acts downstream of Shh signalling during GT outgrowth. Together, these data reveal conserved and divergent features of the developmental programmes that trigger GT and limb bud development.
Finally, Seifert et al. identify two temporal phases for Shh function during anogenital development (see p. ). Shh, they report, coordinates the outgrowth and patterning of the GT and the septation of the embryonic cloaca during the ‘anogenital’ phase. Then, during the ‘external genital phase’, Shh regulates only the development of the external genitalia. Other experiments show that Shh signals directly to the ectoderm to maintain a closed urethral tube, thus highlighting a new role for genital ectoderm in urethragenesis. Overall, these results provide insights into the causes of anogenital malformations, some of the most common human congenital abnormalities.
