Sex-Dependent and -Independent Mechanisms in External Genitalia Development

Genital malformation, including hypospadias, represents the second most common male birth defect after cardiac defect. In the past 50 years, hypospadias incidence has doubled along with other male reproductive problems. It is suspected that fetal exposure to endocrine disruptors may have contributed to this increase. However, our understanding of basic genitalia development in general, including hormone-mediated genital differentiation, is still very limited. A complete understanding of genetic pathways governing genital development and masculinization and how perturbations of these pathways lead to genital malformations will have important applications to improve global health. In the past 20 years, comprehensive genetic analyses on genital tubercle development in knockout and transgenic mice have revealed critical signaling pathways regulating both the initial genital outgrowth phase and the subsequent hormone-dependent genital masculinization phase. Interestingly, some signaling pathways, such as Wnt, Hh, and Fgf, are required during both phases of genital development. In this chapter, we will review genitalia development in mice as well as the effect of endocrine disruption on genitalia development. A thorough dissection of genetic pathways regulating posterior embryonic development should allow us to better understand gene-environment interactions that influence genitalia development and hypospadias formation.