The male urethra: spatiotemporal distribution of molecular markers during early development

The organogenesis of the male human urethra is still a subject of controversy. Although many studies have been conducted, the mechanisms of urethral development still need further investigation to clarify questions concerning the sequences in its development. Our aim has been to elucidate the spatiotemporal distribution of relevant immunohistochemical indicators during the development of the male urethral epithelium and its adjacent mesenchyme. Therefore, we analyzed male human embryos and foetuses between the 6th and 15th week after fertilization using histological and immunohistochemical methods. Monoclonal antibodies raised against cytokeratins (CKs) 7, 8, 13 and 17 as well as Ki67, E-Cadherin, p63, uroplakin III, smooth muscle actin (SMA) and vimentin were applied. Our results revealed that epithelial differentiation starts prior to the rupture of the cloacal membrane. At weeks (W) 8-9 the epithelium became transitional over the whole length of the elongating urethra. The urothelial staining pattern of uroplakin III receded continually, and, at the end of W 11, it had receded in proximal direction to the bladder neck comparable to the epithelial appearance in adults. The urogenital sinus epithelium provided the Wolffian duct with p63-positive cells, leading to the suggestion that the development of the male inner genitals requires a cellular stimulus by this very epithelium. CK 17-positive cells, which were described as epithelial stem cells, could be found in the extending urethral plate. This facilitates new insight into the pathogenesis and treatment of hypospadias, which is one of the most common malformations in newborn males.