Molecular analysis of external genitalia formation: the role of fibroblastgrowth factor (Fgf) genes during genital tubercle formation

The molecular mechanisms underlying the development of the external genital ia in mammals have been very little examined. Recent gene knockout studies have suggested that the developmental processes of its anlage, the genital tubercle (GT), have much in common with those of limb buds. The Fgf genes h ave been postulated as regulating several downstream genes during organogen esis. Fgf8 was expressed in the distal urethral plate epithelium of the gen ital tubercle (GT) together with other markers such as the Msx1, Fgf10, Hox d13 and Bmp4 expressed in the mesenchyme. To analyze the role of the FGF sy stem during GT formation, an in vitro organ culture system was utilized. It is suggested that the distal urethral plate epithelium of GT, the Fgf8-exp ressing region, regulates the outgrowth of GT. Ectopic application of FGF8 beads to the murine GT induced mesenchymal gene expression, and also promot ed the outgrowth of the GT. Experiments utilizing anti-FGF neutralizing ant ibody suggested a growth-promoting role for FGF protein(s) in GT outgrowth. In contrast, despite its vital role during limb-bud formation, Fgf10 appea rs not to be primarily essential for initial outgrowth of GT, as extrapolat ed from Fgf10(-/-) GTs, However, the abnormal external genitalia developmen t of Fgf10(-/-) perinatal mice suggested the importance of Fgf10 in the dev elopment of the glans penis and the glans clitoridis. These results suggest that the FGF system is a key element in orchestrating GT development.