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First published online November 11, 2009
doi: 10.1242/10.1242/dev.039438

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Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

Shinichi Miyagawa^1,2, Anne Moon^3,*, Ryuma Haraguchi^2,*, Chie Inoue⁴, Masayo Harada¹, Chiaki Nakahara⁴, Kentaro Suzuki¹, Daisuke Matsumaru⁴, Takehito Kaneko², Isao Matsuo⁵, Lei Yang⁶, Makoto M. Taketo⁷, Taisen Iguchi⁸, Sylvia M. Evans⁹ and Gen Yamada^1,4,

¹ Institute of Molecular Embryology and Genetics, Global COE ‘Cell Fate Regulation Research and Education Unit’, Kumamoto University, Kumamoto 860-0811, Japan
² Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
³ Departments of Pediatrics, Neurobiology and Anatomy, and Human Genetics, University of Utah, UT 84112, USA
⁴ Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
⁵ Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan
⁶ Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
⁷ Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
⁸ National Institutes of Natural Sciences, Okazaki 444-8787, Japan
⁹ Skaggs School of Pharmacy, University of California, San Diego, CA 92093, USA

Author for correspondence (gensan{at}gpo.kumamoto-u.ac.jp)

Accepted October 14, 2009

Embryonic appendicular structures, such as the limb buds and the developing external genitalia, are suitable models with which to analyze the reciprocal interactions of growth factors in the regulation of outgrowth. Although several studies have evaluated the individual functions of different growth factors in appendicular growth, the coordinated function and integration of input from multiple signaling cascades is poorly understood. We demonstrate that a novel signaling cascade governs formation of the embryonic external genitalia [genital tubercle (GT)]. We show that the dosage of Shh signal is tightly associated with subsequent levels of Wnt/β-catenin activity and the extent of external genitalia outgrowth. In Shh-null mouse embryos, both expression of Wnt ligands and Wnt/β-catenin signaling activity are downregulated. β-catenin gain-of-function mutation rescues defective GT outgrowth and Fgf8 expression in Shh-null embryos. These data indicate that Wnt/β-catenin signaling in the distal urethral epithelium acts downstream of Shh signaling during GT outgrowth. The current data also suggest that Wnt/β-catenin regulates Fgf8 expression via Lef/Tcf binding sites in a 3' conserved enhancer. Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among multiple Fgfs in GT development. Our results provide new insights into the integration of growth factor signaling in the appendicular developmental programs that regulate external genitalia development.

Key words: External genitalia, Genetic cascade, Hedgehog, Fgf, β-catenin (Ctnnb1), Cloaca, Appendages, Mouse

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