Developmental genetics of the external genitalia.

The incidence of congenital malformation of the urogenital system is second only to that of the cardiovascular system, yet comparatively little is known about the cellular and molecular mechanisms that regulate urogenital organogenesis. In this chapter, I review recent advances in the developmental biology of the external genitalia, and discuss the implications of this work for our understanding of hypospadias. The majority of research into external genital development and hypospadias has focused on the endocrine system, particularly on the role of androgens (see accompanying chapters in this volume). A relatively unexplored area of genital morphogenesis is the early, genetically controlled process of pattern formation, when genital tubercle outgrowth and three-dimensional patterning occurs (Figure 1). These processes occur in the absence of endocrine signals, and identification of the molecular mechanisms of early genital development is crucial to our understanding of congenital anomalies. One of the surprises of comparative developmental studies is that evolution has been relatively conservative; the same genetic cassettes are involved in development of eyes, limbs and nerves, for example, in animals as diverse as flies and humans. The knowledge that genetic circuits have been repeatedly co-opted during the evolution of embryonic development provides a springboard for investigating the urogenital system. We have used the vertebrate limb as a paradigm for investigating the mechanisms involved in external genital development. Limbs and external genitalia undergo many similar morphogenetic processes, and we have hypothesized that the same molecular mechanisms may operate during development of the limb bud and the genital tubercle. Here I report on some of the initial tests of this hypothesis.