INVESTIGATIVE UROLOGY

Sonic hedgehog signaling from the urethral epithelium controls external genital development
Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn MJ
Division of Zoology, University of Reading, Whiteknights, United Kingdom
Dev Biol. 2002; 247:26-46

• External genital development begins with formation of paired genital swellings, which develop into the genital tubercle. Proximodistal outgrowth and axial patterning of the genital tubercle are coordinated to give rise to the penis or clitoris. The genital tubercle consists of lateral plate mesoderm, surface ectoderm, and endodermal urethral epithelium derived from the urogenital sinus. We have investigated the molecular control of external genital development in the mouse embryo. Previous work has shown that the genital tubercle has polarizing activity, but the precise location of this activity within the tubercle is unknown. We reasoned that if the tubercle itself is patterned by a specialized signaling region, then polarizing activity may be restricted to a subset of cells. Transplantation of urethral epithelium, but not genital mesenchyme, to chick limbs results in mirror-image duplication of the digits. Moreover, when grafted to chick limbs, the urethral plate orchestrates morphogenetic movements normally associated with external genital development. Signaling activity is therefore restricted to urethral plate cells. Before and during normal genital tubercle outgrowth, urethral plate epithelium expresses Sonic hedgehog (Shh). In mice with a targeted deletion of Shh, external genitalia are absent. Genital swellings are initiated, but outgrowth is not maintained. In the absence of Shh signaling, Fgf8, Bmp2, Bmp4, Fgf10, and Wnt5a are downregulated, and apoptosis is enhanced in the genitalia. These results identify the urethral epithelium as a signaling center of the genital tubercle, and demonstrate that Shh from the urethral epithelium is required for outgrowth, patterning, and cell survival in the developing external genitalia.
  
  
• Editorial Comment
  The literature concerning external genital development is controversial, owing largely to inconsistent descriptions of genital development. Development of penile urethra has been a particular area of controversy, with such fundamental issues as the embryonic origin of the distal urethral plate and morphogenesis of the tubular urethra remaining unclear. Despite external genital defects are among the most common congenital anomalies, the molecular mechanisms controlling early stages of external genitalia development is not well understood. Recent findings showed that the spongy urethra presents regional differences regarding to extracellular matrix molecules (1), and this could have a key role during urethral development because a normal interaction between epithelial and mesenchymal tissues in the tubercle is required for normal genital development.
  The authors have provided the most accurate and comprehensive study of the embryology of the mouse external genitalia. The authors did not detect, at any stage studied, an ectodermal ingrowth from the apex of the mouse genital tubercle. This contrasts with previous reports that the distal urethra forms by apical ectodermal invagination.
  However, the most impressing finding in the present paper is the superb description of the key role of Shh genes in the external genital development. Furthermore, these genes regulate the expression of several cytokines (i.e., FGF family). Another strong point in the present paper is the clear evidence showed by the authors that the urethral epithelium, but not genital mesenchyme, has polarizing activity. The authors’ results clearly identified the urethral epithelium as a signaling region in the genital tubercle, implicated Shh genes as the key urethral signal, and showed that Shh is essential for external development.

Reference
1. Da Silva EA, Sampaio FJB, Ortiz V, Cardoso LE: Regional differences in the extracellular matrix of the
human spongy urethra as evidenced by the composition of glycosaminoglycans. J Urol. 2002; 167:2183-7

Dr. E. Alexsandro da Silva
Urogenital Research Unit
State University of Rio de Janeiro
Rio de Janeiro, RJ, Brazil