Ontogeny of the male urethra: Theory of endodermal differentiation

The most widely accepted mechanism of male urethral development proposes th at the urethral plate is elevated by urethral folds which fuse ventrally in a proximal-to-distal sequence. Unlike its proximal counterpart, the urethr a which forms within the glans is lined by a stratified squamous epithelium and has a more controversial development. One theory supports the idea tha t fusion of the urethral folds extends all the way to the tip of the glans. Another theory suggests that a solid ectodermal in growth of epidermis can alizes the glandar urethra. We hypothesized that the use of immunohistochem ical staining and tissue recombinant grafting would delineate the epithelia involved and lend clues to their origin. Thirty-six human fetal phallic sp ecimens of gestational ages 5-22 weeks were sectioned and stained immunohis tochemically with antibodies raised against different cytokeratins. Evaluat ion of the sections showed that the urethral plate, an extension of the uro genital sinus, extended to the tip of the phallus and maintained patency an d continuity throughout the process of urethral development. The entire ure thra, including the glans portion, was formed by dorsal extension and disin tegration of the urethal plate combined with ventral growth and fusion of t he urethral folds. Sections of the distal glandar urethra showed no evidenc e of a solid ectodermal ingrowth. Rather, immunostaining results at differe nt ages suggested differentiation of the endodermal urethral plate into a s tratified squamous epithelium. To determine whether urothelium could be ind uced to express a stratified squamous phenotype, mouse fetal bladder epithe lium was combined with rat fetal genital tubercle mesenchyme and grown unde r the renal capsule of athymic mice. The bladder epithelium differentiated into a stratified squamous epithelium. Thus, proper mesenchymal signaling m ay induce differentiation of urothelium into a stratified squamous phenotyp e, such as during development of the urethra of the glans penis.