Baskin L S, Erol A, Jegatheesan P, Li Y, Liu W, Cunha G R
Department of Urology, University of California School of Medicine, San Francisco, CA 94143-0738, USA.
Cell Tissue Res. 2001 Sep;305(3):379-87. doi: 10.1007/s004410000345.
Knowledge of the formation of the normal male urethra may elucidate the etiology of hypospadias. We describe urethral formation in the mouse, show the similarities and relevance to human urethral development, and introduce the concept of the epithelial seam formation and remodeling during urethral formation. Three mechanisms may account for epithelial seam formation: (1) epithelial-mesenchymal transformation similar to that described in the fusion of the palatal shelves, (2) apoptosis, and/or (3) tissue remodeling via cellular migration. Urethral development in the embryonic mouse (14-21 days of gestation) was compared with urethral formation in embryonic human specimens (8-16 weeks of gestation) by using histology, immunohistochemistry, and three-dimensional reconstruction. The urethra forms by fusion of the epithelial edges of the urethral folds, giving a midline epithelial seam. The epithelial seam is remodeled via cellular migration into a centrally located urethra and ventrally displaced remnant of epithelial cells. The epithelial seam is remodeled by narrowing approximately at its midpoint, with subsequent epithelial migration into the urethra or penile skin. The epithelial cells are replaced by mesenchymal cells. This remodeling seam displays a narrow band (approximately 30 microns 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 vimentin). Urethral seam formation occurs in both the mouse and the human. Our data in the mouse support the hypothesis that seam transformation occurs via cellular migration and not by epithelial mesenchymal transformation or epithelial apoptosis. We postulate that disruption of epithelial fusion remodeling, and cellular migration leads to hypospadias.
了解正常男性尿道的形成过程可能有助于阐明尿道下裂的病因。我们描述了小鼠尿道的形成过程，展示了其与人类尿道发育的相似性和相关性，并介绍了尿道形成过程中上皮缝形成和重塑的概念。上皮缝形成可能有三种机制：（1）类似于腭突融合中所描述的上皮-间充质转化；（2）细胞凋亡；和/或（3）通过细胞迁移进行的组织重塑。通过组织学、免疫组织化学和三维重建，将胚胎小鼠（妊娠14 - 21天）的尿道发育与胚胎人类标本（妊娠8 - 16周）的尿道形成进行了比较。尿道由尿道褶的上皮边缘融合形成，形成一条中线的上皮缝。上皮缝通过细胞迁移重塑为位于中央的尿道和向腹侧移位的上皮细胞残余。上皮缝在其大约中点处变窄而重塑，随后上皮细胞迁移到尿道或阴茎皮肤中。上皮细胞被间充质细胞取代。这条重塑的缝显示出一条窄带（约30微米宽）的凋亡活性，对应于间充质细胞而非上皮细胞。未发现细胞角蛋白和间充质标志物（肌动蛋白或波形蛋白）共表达的证据。小鼠和人类均会发生尿道缝形成。我们在小鼠中的数据支持这样的假说，即缝的转化是通过细胞迁移发生的，而非上皮-间充质转化或上皮凋亡。我们推测上皮融合重塑和细胞迁移的破坏会导致尿道下裂。
