International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I6. Molecular Analysis of External Genitalia Formation: Control of Morphogenesis of Genital Tubercle by shh and FGF

R. Haraguchi1, J. Motoyama2, C.C. Hui3, K. Suzuki1, M. Kamikawa1, S.Makino44, T.Shiroishi4,W. Gaffield5, Y. Ogino1, Y.Sato1, N.Takeda1 and G. Yamada1*
1Center for Animal Resources and Development (CARD), Kumamoto Univ, Honjo 2-2-1, Kumamoto 860-0811, Japan, 2Brain Science Inst (RIKEN), 3Program in Deve Biol, The Hosp for Sick Children, Univ. of Toronto, Canada, 4Lab Mamm Genet,Natl Inst. Genet, Mishima, Japan, 5Western Regional Res Center, CA
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Our group has been working on the roles of several key signaling molecules during murine external genitalia formation. 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. 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 genital tubercle (GT) along with other markers such as the Msx1, Fgf10, Hoxd13, and Bmp4 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 is suggested that the distal urethral plate epithelium of GT regulates the outgrowth of GT. The region was thus suggested as a candidate region for the signaling center for GT development. Ectopic application of FGF8 beads induced mesenchymal gene expression, and also promoted the outgrowth of the GT. Experiments utilizing anti-FGF, anti-shh neutralizing antibody were performed. In contrast, the Fgf10 gene appears not to be primarily essential for initial outgrowth of GT, as extrapolated from Fgf10 mutant GTs. 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. These results suggest that the FGF system is a key element in orchestrating GT development. Our recent analysis on FGF and shh system will be presented.

Ref. Haraguchi et. al. Molecular analysis of external genitalia formation. Development 127(11):2471-2479, (2000).

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