Yamada, G. Yamada: Molecular analysis of murine external genitalia formation: Control of morphogenesis of genital tubercle by shh and FGF system.

Recent gene KO studies have suggested that the developmental process of the anlage, the genital tubercle (GT), has much in common with those of limb buds. However, except for some previous genetic studies, systematic approach on several regulatory molecules during GT formation has not been performed. The shh and fibroblast growth factor (Fgf) genes have been postulated as regulating several downstream genes during organogenesis. The Fgf8 gene was expressed in the distal urethral plate epithelium of the GT along with other marker genes expressed in the mesenchyme. The Shh gene was found to be expressed in the urethral plate epithelium . The urogenital expression of the Shh gene was also reported by Bitgood and McMahon. To functionally analyze the role of the FGF and shh system during GT formation, an in vitro organ culture system was utilized. It was suggested that the distal urethral plate epithelium of GT, the Fgf8 gene expressing region, regulates the outgrowth of GT. The region was thus suggested as a candidate region for the signaling center during GT development. Ectopic application of FGF8 beads to the murine GT induced mesenchymal gene expression, and also promoted the outgrowth of the GT. Experiments utilizing anti-FGF neutralizing antibody suggested a growth-promoting role for FGF protein(s) in GT outgrowth. In contrast, the Fgf10 gene appears not to be primarily essential for initial outgrowth of GT despite its vital role during limb bud formation. Rather, the abnormal external genitalia development of Fgf10 mutant perinatal mice suggested the importance of the Fgf10 gene in the development of the glans penis and the glans clitoridis. Our recent analysis on FGF and shh system will be presented. These data are expected to contribute elucidating ” a model plan” for organogenesis of external genitalia and other organs such as limbs.