Meeting Abstract
The cellular and molecular genetic mechanisms of external genital development are beginning to be elucidated from studies of the mouse genital tubercle, an embryonic appendage adjacent to the cloaca that is the precursor of the penis and clitoris. At early stages, patterning of the genital tubercle is similar in males and females. Sexual differentiation of the genitalia occurs at later stages, when sex-specific hormonal cues interact with developmental control genes to masculinize or feminize the genital tubercle, although the nature of these interactions remains unclear. Congenital malformations of external genitalia are among the most common birth defects in humans, with hypospadias, a failure of urethral tube closure, affecting ~1:250 live births. Affected children can have mislocalized, multiple or oversized urethral openings, and males with severe hypospadias are born with ambiguous genitalia. Despite this, there is a relatively poor understanding of the cellular and molecular mechanisms that control development of external genitalia. Prenatal exposures to environmental endocrine disrupting chemicals (EDCs) may play a causal role in the high incidence of genitourinary malformations. How the developmental genetic mechanisms that pattern the genital tubercle are affected by exposure to EDCs is largely unknown. We are integrating mouse developmental genetics, genomics, and environmental toxicology in order to identify causes of genitourinary malformations and the targets of EDCs in the genital tubercle. From an evolutionary perspective, genitalia evolve faster than any other organ system, which has led to striking diversity of morphological forms. This natural diversity provides a rich opportunity to dissect the mechanisms of genital evolution and to investigate the evolutionary underpinnings of external genital development and congenital malformations.
