Temporal, spatial, and genetic regulation of external genitalia development

Fertilization requires the physical combination of gametes, and terrestrial mammals necessitated the evolution of genitalia capable of successfully completing the fertilization process in a non-aqueous environment. Thus, the male mammalian external genitalia evolved as an outgrowth from the body, an appendage sufficient to fertilize eggs housed deep inside the female. In this way, sexual dimorphism of mammalian genitalia became highly pronounced. This highly complex evolutionary divergence both from aqueous fertilization, as well as divergence between the sexes of terrestrial mammals, required exquisitely coordinated, novel patterns of gene expression to regulate the spatial and temporal events governing external genitalia development. Recent studies delineating the genetic regulation of external genitalia development, largely focusing on development of the murine genital tubercle, have vastly enlightened the field of reproductive developmental biology. Murine homologs of human genes have been selectively deleted in the mouse, either in the whole body or using tissue-specific and temporally-specific genetic drivers. The defects in outgrowth and urethral tubularization subsequent to the deletion of specific genes in the developing murine external genitalia delineates which genes are required in which compartments and at what times. This review details how these murine genetic models have created a somewhat modest but rapidly growing library of knowledge detailing the spatial-temporal genetic regulation of external genitalia development.