Knowledge of the formation of the normal male urethra may elucidate the eti
ology of hypospadias. We describe urethral formation in the mouse, show the
similarities and relevance to human urethral development, and introduce th
e concept of the epithelial seam formation and remodeling during urethral f
ormation. Three mechanisms may account for epithelial seam formation: (1) e
pithelial-mesenchymal transformation similar to that described in the fusio
n of the palatal shelves, (2) apoptosis, and/or (3) tissue remodeling via c
ellular migration. Urethral development in the embryonic mouse (14-21 days
of gestation) was compared with urethral formation in embryonic human speci
mens (8-16 weeks of gestation) by using histology, immunohistochemistry, an
d three-dimensional reconstruction. The urethra forms by fusion of the epit
helial edges of the urethral folds, giving a midline epithelial seam. The e
pithelial seam is remodeled via cellular migration into a centrally located
urethra and ventrally displaced remnant of epithelial cells. The epithelia
l seam is remodeled by narrowing approximately at its midpoint, with subseq
uent epithelial migration into the urethra or penile skin. The epithelial c
ells are replaced by mesenchymal cells. This remodeling seam displays a nar
row band (approximately 30 mum wide) of apoptotic activity corresponding to
the mesenchymal cells and not to epithelial cells. No evidence was seen of
the co-expression of cytokeratin and mesenchymal markers (actin or vimenti
n). Urethral seam formation occurs in both the mouse and the human. Our dat
a in the mouse support the hypothesis that seam transformation occurs via c
ellular migration and not by epithelial mesenchymal transformation or epith
elial apoptosis. We postulate that disruption of epithelial fusion, remodel
ing, and cellular migration leads to hypospadias.