Anat Embryol (2004) 208:479–486 DOI 10.1007/s00429-004-0419-9 ORIGINAL ARTICLE Yoshihiko Satoh · Ryuma Haraguchi · Tracy J. Wright · Suzanne L. Mansour · Juha Partanen · Mohammad K. Hajihosseini · Veraragavan P. Eswarakumar · Peter Lonai · Gen Yamada Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors Accepted: 21 July 2004 / Published online: 31 August 2004  Springer-Verlag 2004 Abstract Members of the fibroblast growth factor (FGF) family play diverse roles during the development and patterning of various organs. In human and mice, 22 FGFs and four receptors derived from several splice variants are present. Redundant expression and function of FGF genes in organogenesis have been reported, but their roles in embryonic external genitalia, genital tubercle (GT), de- velopment have not been studied in detail. To address the role of FGF during external genitalia development, we have analyzed the expression of FGF genes (Fgf8, 9, 10) and receptor genes (Fgfr1, r2IIIb, r2IIIc) in GT of mice. Furthermore, Fgf10 and Fgfr2IIIb mutant mice were an- alyzed to elucidate their roles in embryonic external genitalia development. Fgfr2IIIb was expressed in ure- thral plate epithelium during GT development. Fgfr2IIIb mutant mice display urethral dysmorphogenesis. Marker gene analysis for urethral plate and bilateral mesenchymal formation suggests the existence of epithelial-mesenchy- mal interaction during urethral morphogenesis. Therefore, FGF10/FGFR2IIIb signals seem to constitute a develop- mental cascade for such morphogenesis. Keywords Fibroblast growth factor · Genital tubercle · Urethra · Hypospadias · External genitalia Introduction The external genital anlage, hereafter referred to as the genital tubercle (GT), differentiates into a penis in males and a clitoris in females (Murakami and Mizuno 1986). The proximodistal elongation of the GT is thought to require an orchestrated set of interactions involving sev- eral growth and transcription factors. Epithelial-mesen- chymal interactions play an essential role in regulating a wide variety of developmental processes (Thesleff et al. 1991; Tickle and Eichele 1994; Johnson and Tabin 1997; Hogan 1999; Kurzrock et al. 1999; Othman-Hassan et al. 2001). Such signaling governs many aspects of organo- genesis, from the initiation of organ development to dif- ferentiation (Grothe et al. 1996; Dassule and McMahon 1998; Tucker et al. 1999). The fibroblast growth factor (FGF) signaling pathway regulates epithelial-mesenchymal interactions during the development of many organs (Orr-Urtreger et al. 1991; Peters et al. 1992; De Moerlooze et al. 2000; Macatee et al. 2003). The Fgfs comprise a 22-member gene family encoding heparan sulfate-binding proteins that signal through transmembrane receptors encoded by four genes. FGF receptors (FGFRs) are composed of two or three immunoglobulin-like loops in the external domain, a transmembrane segment, and a ligand-activated cyto- plasmic tyrosine kinase domain. Fgfr1, -2, and -3 mRNAs are alternatively spliced within the region encoding the Y. Satoh and R. Haraguchi contributed equally to this work Y. Satoh · R. Haraguchi · G. Yamada ( ) ) Center for Animal Resources and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, 860-0811 Kumamoto, Japan e-mail: gen@kaiju.medic.kumamoto-u.ac.jp Tel.: +81-96-3736569 Fax: +81-96-3736560 T. J. Wright · S. L. Mansour Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA J. Partanen Institute of Biotechnology, University of Helsinki, Helsinki, Finland M. K. Hajihosseini School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK V. P. Eswarakumar · P. Lonai Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel