Skip to main content

Advertisement

SpringerLink
Log in

Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors

  • Original Article
  • Published:
Anatomy and Embryology Aims and scope Submit manuscript

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), development 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 analyzed to elucidate their roles in embryonic external genitalia development. Fgfr2IIIb was expressed in urethral 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-mesenchymal interaction during urethral morphogenesis. Therefore, FGF10/FGFR2IIIb signals seem to constitute a developmental cascade for such morphogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–H
Fig. 2A–F
Fig. 3A–E
Fig. 4A–F

Similar content being viewed by others

References

  • Arman E, Haffner-Krausz R, Gorivodsky M, Lonai P (1999) Fgfr2 is required for limb outgrowth and lung-branching morphogenesis. Proc Natl Acad Sci USA 96:11895–11899

    Article  CAS  PubMed  Google Scholar 

  • Barlow AJ, Francis-West PH (1997) Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 124:391–398

    CAS  PubMed  Google Scholar 

  • Baskin LS (2004) Hypospadias. Adv Exp Med Biol 545:3-22

    PubMed  Google Scholar 

  • Baskin LS, Liu W, Bastacky J, Yucel S (2004) Anatomical studies of the mouse genital tubercle. Adv Exp Med Biol 545:103–121

    PubMed  Google Scholar 

  • Chen Y, Zhao X (1998) Shaping limbs by apoptosis. J Exp Zool 282:691–702

    Article  CAS  PubMed  Google Scholar 

  • Dassule HR, McMahon AP (1998) Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth. Dev Biol 202:215–227

    Article  CAS  PubMed  Google Scholar 

  • De Moerlooze L, Spencer-Dene B, Revest J, Hajihosseini M, Rosewell I, Dickson C (2000) An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 127:483–492

    PubMed  Google Scholar 

  • Dolle P, Izpisua-Belmonte JC, Brown JM, Tickle C, Duboule D (1991) HOX-4 genes and the morphogenesis of mammalian genitalia. Genes Dev 5:1767–7

    CAS  PubMed  Google Scholar 

  • Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, Baker LA, Henkemeyer M (2004) Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol 271:272–290

    Article  CAS  PubMed  Google Scholar 

  • Duboule D (1994) How to make a limb? Science 266:575–576

    CAS  PubMed  Google Scholar 

  • Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM, Lonai P (2002) The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development 129:3783–3793

    CAS  PubMed  Google Scholar 

  • Ganan Y, Macias D, Duterque-Coquillaud M, Ros MA, Hurle JM (1996) Role of TGF beta s and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 122:2349–2357

    CAS  PubMed  Google Scholar 

  • Grothe C, Brand-Saberi B, Wilting J, Christ B (1996) Fibroblast growth factor receptor 1 in skeletal and heart muscle cells: expression during early avian development and regulation after notochord transplantation. Dev Dyn 206:310–317

    Article  CAS  PubMed  Google Scholar 

  • Hajihosseini MK, Lalioti MD, Arthaud S, Burgar HR, Brown JM, Twigg SR, Wilkie AO, Heath JK (2004) Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics. Development 131:325–335

    Article  CAS  PubMed  Google Scholar 

  • Haraguchi R, Mo R, Hui C, Motoyama J, Makino S, Shiroishi T, Gaffield W, Yamada G (2001) Unique functions of Sonic hedgehog signaling during external genitalia development. Development 128:4241–4250

    CAS  PubMed  Google Scholar 

  • Haraguchi R, Suzuki K, Murakami R, Sakai M, Kamikawa M, Kengaku M, Sekine K, Kawano H, Kato S, Ueno N, Yamada G (2000) Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development 127:2471–2479

    CAS  PubMed  Google Scholar 

  • Hogan BL (1999) Morphogenesis. Cell 96:225–233

    Article  CAS  PubMed  Google Scholar 

  • Hsu TY, Chang SY, Wang TJ, Ou CY, Chen ZH, Hsu PH (2001) Prenatal sonographic appearance of Beare-Stevenson cutis gyrata syndrome: two- and three-dimensional ultrasonographic findings. Prenat Diagn 21:665–667

    Article  CAS  PubMed  Google Scholar 

  • Johnson RL, Tabin CJ (1997) Molecular models for vertebrate limb development. Cell 90:979–990

    Article  CAS  PubMed  Google Scholar 

  • Kawakami Y, Capdevila J, Buscher D, Itoh T, Rodriguez Esteban C, Izpisua Belmonte JC (2001) WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 104:891–900

    Article  CAS  PubMed  Google Scholar 

  • Kurzrock EA, Baskin LS, Li Y, Cunha GR (1999) Epithelial-mesenchymal interactions in development of the mouse fetal genital tubercle. Cells Tissues Organs 164:125–130

    Article  CAS  PubMed  Google Scholar 

  • Macatee TL, Hammond BP, Arenkiel BR, Francis L, Frank DU, Moon AM (2003) Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development 130:6361–6374

    Article  CAS  PubMed  Google Scholar 

  • Min H, Danilenko DM, Scully SA, Bolon B, Ring BD, Tarpley JE, DeRose M, Simonet WS (1998) Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12:3156–3161

    CAS  PubMed  Google Scholar 

  • Morgan EA, Nguyen SB, Scott V, Stadler HS (2003) Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development 130:3095–3109

    Article  CAS  PubMed  Google Scholar 

  • Murakami R, Mizuno T (1986) Proximal-distal sequence of development of the skeletal tissues in the penis of rat and the inductive effect of epithelium. J Embryol Exp Morphol 92:133–143

    CAS  PubMed  Google Scholar 

  • Naiche LA, Papaioannou VE (2003) Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois. Development 130:2681–2693

    Article  CAS  PubMed  Google Scholar 

  • Ng JK, Kawakami Y, Buscher D, Raya A, Itoh T, Koth CM, Rodriguez Esteban C, Rodriguez-Leon J, Garrity DM, Fishman MC, Izpisua Belmonte JC (2002) The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development 129:5161–5170

    CAS  PubMed  Google Scholar 

  • Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N (2000) FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277:643–649

    Article  CAS  PubMed  Google Scholar 

  • Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, Ishimaru Y, Yoshioka H, Kuwana T, Nohno T, Yamasaki M, Itoh N, Noji S (1997) The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. Development 124:2235–2244

    CAS  PubMed  Google Scholar 

  • Ornitz DM, Itoh N (2001) Fibroblast growth factors. Genome Biol 2:REVIEWS3005

    Article  CAS  PubMed  Google Scholar 

  • Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271:15292–15297

    Article  CAS  PubMed  Google Scholar 

  • Orr-Urtreger A, Givol D, Yayon A, Yarden Y, Lonai P (1991) Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development 113:1419-1434

    CAS  PubMed  Google Scholar 

  • Othman-Hassan K, Patel K, Papoutsi M, Rodriguez-Niedenfuhr M, Christ B, Wilting J (2001) Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237:398–409

    Article  CAS  PubMed  Google Scholar 

  • Partanen J, Schwartz L, Rossant J (1998) Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos. Genes Dev 12:2332–2344

    CAS  PubMed  Google Scholar 

  • Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn MJ (2002) Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol 247:26–46

    Article  CAS  PubMed  Google Scholar 

  • Peters KG, Werner S, Chen G, Williams LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114:233–243

    CAS  PubMed  Google Scholar 

  • Plikus M, Wang WP, Liu J, Wang X, Jiang TX, Chuong CM (2004) Morpho-regulation of ectodermal organs: integument pathology and phenotypic variations in K14-Noggin engineered mice through modulation of bone morphogenic protein pathway. Am J Pathol 164:1099–1114

    CAS  PubMed  Google Scholar 

  • Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197

    CAS  PubMed  Google Scholar 

  • Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C (2001) Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol 231:47–62

    Article  CAS  PubMed  Google Scholar 

  • Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, Yagishita N, Matsui D, Koga Y, Itoh N, Kato S (1999) Fgf10 is essential for limb and lung formation. Nat Genet 21:138–141

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Bachiller D, Chen YP, Kamikawa M, Ogi H, Haraguchi R, Ogino Y, Minami Y, Mishina Y, Ahn K, Crenshaw EB, III, Yamada G (2003) Regulation of outgrowth and apoptosis for the terminal appendage: external genitalia: development by concerted actions of BMP signaling. Development 130:6209–6220

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Ogino Y, Murakami R, Satoh Y, Bachiller D, Yamada G (2002) Embryonic development of mouse external genitalia: insights into a unique mode of organogenesis. Evol Dev 4:133–141

    Article  PubMed  Google Scholar 

  • Thesleff I, Partanen AM, Vainio S (1991) Epithelial-mesenchymal interactions in tooth morphogenesis: the roles of extracellular matrix, growth factors, and cell surface receptors. J Craniofac Genet Dev Biol 11:229–237

    CAS  PubMed  Google Scholar 

  • Tickle C, Eichele G (1994) Vertebrate limb development. Ann Rev Cell Biol 10:121–152

    CAS  PubMed  Google Scholar 

  • Tucker AS, Yamada G, Grigoriou M, Pachnis V, Sharpe PT (1999) Fgf-8 determines rostral-caudal polarity in the first branchial arch. Development 126:51–61

    CAS  PubMed  Google Scholar 

  • van der Werff JF, Nievelstein RA, Brands E, Luijsterburg AJ, Vermeij-Keers C (2000) Normal development of the male anterior urethra. Teratology 61:172–183

    Article  PubMed  Google Scholar 

  • Vargas RA, Maegawa GH, Taucher SC, Leite JC, Sanz P, Cifuentes J, Parra M, Munoz H, Maranduba CM, Passos-Bueno MR (2003) Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis. Am J Med Genet 121:41–46

    Article  Google Scholar 

  • Wilkinson DG (1995) RNA detection using non-radioactive in situ hybridization. Curr Opin Biotechnol 6:20–23

    Article  CAS  PubMed  Google Scholar 

  • Wright TJ, Mansour SL (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development 130:3379–3390

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Weinstein M, Li C, Naski M, Cohen RI, Ornitz DM, Leder P, Deng C (1998) Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125:753–765

    CAS  PubMed  Google Scholar 

  • Yamada G, Satoh Y, Baskin LS, Cunha GR (2003) Cellular and molecular mechanisms of development of the external genitalia. Differentiation 71:445–460

    Article  PubMed  Google Scholar 

  • Yamaguchi TP, Bradley A, McMahon AP, Jones S (1999) A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development 126:1211–1223

    CAS  PubMed  Google Scholar 

  • Yonei-Tamura S, Endo T, Yajima H, Ohuchi H, Ide H, Tamura K (1999) FGF7 and FGF10 directly induce the apical ectodermal ridge in chick embryos. Dev Biol 211:133–143

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Drs. John K. Heath, Clive Dickson, Tsutomu Ogata, Shigeaki Kato, Janet Rossant, Chi-Chung Hui, Yiping Chen, Gail Martin, Cheng-Ming Chuong, Brigid Hogan, Uli Ruether, Karen M. Lyons, Elaine Fuchs, Nobuyuki Itoh, Anne M. Moon, and David Ornitz for reagents and/or suggestions, and Takashi Tanaharu, Ryu Gejima, Daisuke Sasagawa, and Shiho Kitagawa for assistance. This research was supported by a Grant-in-Aid for Scientific Research on Priority Areas (1), General Promotion of Cancer Research in Japan, Mechanisms of Sex Differentiation, and by the 21st Century COE Research Program and Child Health and Development (14C-1) from the Ministry of Health, Labour and Welfare.

Author information

Authors and Affiliations

  1. Center for Animal Resources and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, 860-0811, Kumamoto, Japan

    Yoshihiko Satoh, Ryuma Haraguchi & Gen Yamada

  2. Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA

    Tracy J. Wright & Suzanne L. Mansour

  3. Institute of Biotechnology, University of Helsinki, Helsinki, Finland

    Juha Partanen

  4. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK

    Mohammad K. Hajihosseini

  5. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    Veraragavan P. Eswarakumar & Peter Lonai

Authors
  1. Yoshihiko Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryuma Haraguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tracy J. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suzanne L. Mansour
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juha Partanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad K. Hajihosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Veraragavan P. Eswarakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Lonai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gen Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gen Yamada.

Additional information

Y. Satoh and R. Haraguchi contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Satoh, Y., Haraguchi, R., Wright, T.J. et al. Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors. Anat Embryol 208, 479–486 (2004). https://doi.org/10.1007/s00429-004-0419-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-004-0419-9

Keywords

Search

Navigation