{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:23:07Z","timestamp":1784697787096,"version":"3.55.0"},"reference-count":58,"publisher":"The Company of Biologists","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,6,15]]},"abstract":"<jats:p>Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis. In the genital tubercle, the embryonic precursor of the penis and clitoris, Fgfr2 is expressed in two epithelial populations: the endodermally derived urethral epithelium and the ectodermally derived surface epithelium. Here, we investigate the tissue-specific roles of Fgfr2 in external genital development by generating conditional deletions of Fgfr2 in each of these cell types. Conditional deletion of Fgfr2 results in two distinct phenotypes: endodermal Fgfr2 deletion causes mild hypospadias and inhibits maturation of a complex urethral epithelium, whereas loss of ectodermal Fgfr2 results in severe hypospadias and absence of the ventral prepuce. Although these cell type-specific mutants exhibit distinctive genital anomalies, cellular analysis reveals that Fgfr2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm. The unexpected finding that ectodermal deletion of Fgfr2 results in the most severe hypospadias highlights a major role for Fgfr2 in the developing genital surface epithelium, where epithelial maturation is required for maintenance of a closed urethral tube. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity.<\/jats:p>","DOI":"10.1242\/dev.119891","type":"journal-article","created":{"date-parts":[[2015,6,16]],"date-time":"2015-06-16T11:19:20Z","timestamp":1434453560000},"page":"2203-2212","source":"Crossref","is-referenced-by-count":47,"title":["Tissue-specific roles of <i>Fgfr2<\/i> in development of the external genitalia"],"prefix":"10.1242","volume":"142","author":[{"given":"Marissa L.","family":"Gredler","sequence":"first","affiliation":[{"name":"Department of Biology, UF Genetics Institute, University of Florida, PO Box 103610, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley W.","family":"Seifert","sequence":"additional","affiliation":[{"name":"Department of Biology, UF Genetics Institute, University of Florida, PO Box 103610, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Cohn","sequence":"additional","affiliation":[{"name":"Department of Biology, UF Genetics Institute, University of Florida, PO Box 103610, Gainesville, FL 32611, USA"},{"name":"Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, University of Florida, PO Box 103610, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608020090400_DEV119891C1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.ydbio.2009.09.024","article-title":"Morphogenesis of epithelial tubes: insights into tube formation, elongation, and elaboration","volume":"341","author":"Andrew","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C2","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1289\/ehp.011091175","article-title":"Hypospadias and endocrine disruption: is there a connection?","volume":"109","author":"Baskin","year":"2001","journal-title":"Child. Health Rev."},{"key":"2021042608020090400_DEV119891C3","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/sj.ejhg.5201777","article-title":"FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias","volume":"15","author":"Beleza-Meireles","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"2021042608020090400_DEV119891C4","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1016\/j.juro.2013.05.061","article-title":"Hypospadias and genes related to genital tubercle and early urethral development","volume":"190","author":"Carmichael","year":"2013","journal-title":"J. Urol."},{"key":"2021042608020090400_DEV119891C5","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.semcdb.2014.03.018","article-title":"Tube fusion: making connections in branched tubular networks","volume":"31","author":"Caviglia","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"2021042608020090400_DEV119891C6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ydbio.2013.12.014","article-title":"Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia","volume":"386","author":"Ching","year":"2014","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C7","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1002\/dvdy.22631","article-title":"Development of the external genitalia: conserved and divergent mechanisms of appendage patterning","volume":"240","author":"Cohn","year":"2011","journal-title":"Dev. Dyn."},{"key":"2021042608020090400_DEV119891C8","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1242\/dev.127.22.4775","article-title":"Sonic hedgehog regulates growth and morphogenesis of the tooth","volume":"127","author":"Dassule","year":"2000","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C9","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0070-2153(07)81003-9","article-title":"Integrating morphogenesis with underlying mechanics and cell biology","volume":"81","author":"Davidson","year":"2008","journal-title":"Curr. Top. Dev. Biol."},{"key":"2021042608020090400_DEV119891C10","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jbiomech.2009.09.010","article-title":"Emergent morphogenesis: elastic mechanics of a self-deforming tissue","volume":"43","author":"Davidson","year":"2010","journal-title":"J. Biomech."},{"key":"2021042608020090400_DEV119891C12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1017\/S1551929500050252","article-title":"Solutions to the problem of substitution of ERL 4221 for vinyl cyclohexene dioxide in Spurr low viscosity embedding formulations","volume":"14","author":"Ellis","year":"2006","journal-title":"Micros. Today"},{"key":"2021042608020090400_DEV119891C13","doi-asserted-by":"publisher","first-page":"3179","DOI":"10.1242\/dev.058602","article-title":"Bone morphogenetic proteins regulate neural tube closure by interacting with the apicobasal polarity pathway","volume":"138","author":"Eom","year":"2011","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C14","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/ng.3063","article-title":"Genome-wide association analyses identify variants in developmental genes associated with hypospadias","volume":"46","author":"Geller","year":"2014","journal-title":"Nat. Genet."},{"key":"2021042608020090400_DEV119891C15","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.semcdb.2014.03.020","article-title":"Controlling cell shape changes during salivary gland tube formation in Drosophila","volume":"31","author":"Girdler","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"2021042608020090400_DEV119891C16","first-page":"413","article-title":"The origin and fate of the urethral plate in man","volume":"88","author":"Glenister","year":"1954","journal-title":"J. Anat."},{"key":"2021042608020090400_DEV119891C17","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1242\/dev.127.11.2471","article-title":"Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation","volume":"127","author":"Haraguchi","year":"2000","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C18","doi-asserted-by":"crossref","first-page":"4241","DOI":"10.1242\/dev.128.21.4241","article-title":"Unique functions of Sonic hedgehog signaling during external genitalia development","volume":"128","author":"Haraguchi","year":"2001","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C19","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.cell.2004.07.024","article-title":"Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities","volume":"118","author":"Harfe","year":"2004","journal-title":"Cell"},{"key":"2021042608020090400_DEV119891C20","volume-title":"Manipulating the Mouse Embryo: A Laboratory Manual","author":"Hogan","year":"1994"},{"key":"2021042608020090400_DEV119891C21","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.bjps.2003.08.018","article-title":"The development of the male genitourinary system: II. The origin and formation of the urethral plate","volume":"57","author":"Hynes","year":"2004","journal-title":"Br. J. Plast. Surg."},{"key":"2021042608020090400_DEV119891C22","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1007\/s10237-012-0423-6","article-title":"Epithelial machines of morphogenesis and their potential application in organ assembly and tissue engineering","volume":"11","author":"Joshi","year":"2012","journal-title":"Biomech. Model. Mechanobiol."},{"key":"2021042608020090400_DEV119891C23","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1111\/j.1365-2605.2008.00899.x","article-title":"Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation?","volume":"32","author":"Kalfa","year":"2009","journal-title":"Int. J. Androl."},{"key":"2021042608020090400_DEV119891C24","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.mce.2011.01.006","article-title":"Hypospadias: interactions between environment and genetics","volume":"335","author":"Kalfa","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021042608020090400_DEV119891C25","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1046\/j.1432-0436.1999.6420115.x","article-title":"Ontogeny of the male urethra: theory of endodermal differentiation","volume":"64","author":"Kurzrock","year":"1999","journal-title":"Differentiation"},{"key":"2021042608020090400_DEV119891C11","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1242\/dev.020586","article-title":"Tissue-specific requirements of \u03b2-catenin in external genitalia development","volume":"135","author":"Lin","year":"2008","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C26","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.yexcr.2013.09.010","article-title":"Luminal matrices: an inside view on organ morphogenesis","volume":"321","author":"Luschnig","year":"2014","journal-title":"Exp. Cell Res."},{"key":"2021042608020090400_DEV119891C27","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.toxlet.2013.10.015","article-title":"Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides","volume":"230","author":"Michalakis","year":"2014","journal-title":"Toxicol. Lett."},{"key":"2021042608020090400_DEV119891C28","doi-asserted-by":"publisher","DOI":"10.4103\/0970-0358.129630","article-title":"Deviation of the penoscrotal median raphe: is it a normal finding or within the spectrum of hypospadias?","volume":"47","author":"Mohan","year":"2014","journal-title":"Indian J. Plast. Surg."},{"key":"2021042608020090400_DEV119891C30","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.juro.2013.09.058","article-title":"Population based nationwide study of hypospadias in Sweden, 1973 to 2009: incidence and risk factors","volume":"191","author":"Nordenvall","year":"2014","journal-title":"J. Urol."},{"key":"2021042608020090400_DEV119891C31","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1542\/peds.100.5.831","article-title":"Hypospadias trends in two US surveillance systems","volume":"100","author":"Paulozzi","year":"1997","journal-title":"Pediatrics"},{"key":"2021042608020090400_DEV119891C32","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1006\/dbio.2002.0668","article-title":"Sonic hedgehog signaling from the urethral epithelium controls external genital development","volume":"247","author":"Perriton","year":"2002","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C33","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1242\/dev.01778","article-title":"Development of the mammalian urethra is controlled by Fgfr2-IIIb","volume":"132","author":"Petiot","year":"2005","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C34","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1002\/dvdy.23866","article-title":"Nonmuscle myosin II regulation of lung epithelial morphology","volume":"241","author":"Plosa","year":"2012","journal-title":"Dev. Dyn."},{"key":"2021042608020090400_DEV119891C35","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.juro.2010.12.066","article-title":"ZEB1 is estrogen responsive in vitro in human foreskin cells and is over expressed in penile skin in patients with severe hypospadias","volume":"185","author":"Qiao","year":"2011","journal-title":"J. Urol."},{"key":"2021042608020090400_DEV119891C36","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1242\/dev.068338","article-title":"Mechanisms of tissue fusion during development","volume":"139","author":"Ray","year":"2012","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C37","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1007\/s00429-004-0419-9","article-title":"Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors","volume":"208","author":"Satoh","year":"2004","journal-title":"Anat. Embryol."},{"key":"2021042608020090400_DEV119891C38","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ydbio.2009.09.009","article-title":"Apical constriction: a cell shape change that can drive morphogenesis","volume":"341","author":"Sawyer","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C39","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.ydbio.2008.03.017","article-title":"Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum","volume":"318","author":"Seifert","year":"2008","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C40","doi-asserted-by":"publisher","first-page":"3949","DOI":"10.1242\/dev.042291","article-title":"Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development","volume":"136","author":"Seifert","year":"2009","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C41","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/ncomms1020","article-title":"Sonic hedgehog controls growth of external genitalia by regulating cell cycle kinetics","volume":"1","author":"Seifert","year":"2010","journal-title":"Nat. Commun."},{"key":"2021042608020090400_DEV119891C42","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/5007","article-title":"Generalized lacZ expression with the ROSA26 Cre reporter strain","volume":"21","author":"Soriano","year":"1999","journal-title":"Nat. Genet."},{"key":"2021042608020090400_DEV119891C43","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1080\/08977190500361697","article-title":"Ligands to FGF receptor 2-IIIb induce proliferation, motility, protection from cell death and cytoskeletal rearrangements in epithelial ovarian cancer cell lines","volume":"24","author":"Steele","year":"2006","journal-title":"Growth Factors"},{"key":"2021042608020090400_DEV119891C44","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/75644","article-title":"Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development","volume":"25","author":"Sun","year":"2000","journal-title":"Nat. Genet."},{"key":"2021042608020090400_DEV119891C45","doi-asserted-by":"publisher","first-page":"e15392","DOI":"10.1371\/journal.pone.0015392","article-title":"Identification of de novo copy number variants associated with human disorders of sexual development","volume":"5","author":"Tannour-Louet","year":"2010","journal-title":"PLoS ONE"},{"key":"2021042608020090400_DEV119891C46","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/nm.3580","article-title":"Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action","volume":"20","author":"Tannour-Louet","year":"2014","journal-title":"Nat. Med."},{"key":"2021042608020090400_DEV119891C47","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/bdra.20707","article-title":"Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection","volume":"88","author":"Toppari","year":"2010","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"2021042608020090400_DEV119891C48","volume-title":"Hypospadias. Leiden","author":"Van der Meulen","year":"1964"},{"key":"2021042608020090400_DEV119891C49","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1002\/(SICI)1096-9926(200003)61:3&lt;172::AID-TERA4&gt;3.0.CO;2-B","article-title":"Normal development of the male anterior urethra","volume":"61","author":"Van der Werff","year":"2000","journal-title":"Teratology"},{"key":"2021042608020090400_DEV119891C50","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1093\/humupd\/dms002","article-title":"Aetiology of hypospadias: a systematic review of genes and environment","volume":"18","author":"Van der Zanden","year":"2012","journal-title":"Hum. Reprod. Update"},{"key":"2021042608020090400_DEV119891C51","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nrm1890","article-title":"Local force and geometry sensing regulate cell functions","volume":"7","author":"Vogel","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042608020090400_DEV119891C52","doi-asserted-by":"publisher","first-page":"E1953","DOI":"10.1210\/jc.2011-0511","article-title":"Evidence for epigenetic abnormalities of the androgen receptor gene in foreskin from children with hypospadias","volume":"96","author":"Vottero","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021042608020090400_DEV119891C53","doi-asserted-by":"publisher","first-page":"499","DOI":"10.2164\/jandrol.108.004945","article-title":"Endocrine disruptors, genital development, and hypospadias","volume":"29","author":"Wang","year":"2008","journal-title":"J. Androl."},{"key":"2021042608020090400_DEV119891C54","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/bdra.23306","article-title":"Geographic analysis of individual and environmental risk factors for hypospadias births","volume":"100","author":"Winston","year":"2014","journal-title":"Birth Defects Res. Clin. Mol. Teratol."},{"key":"2021042608020090400_DEV119891C55","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.juro.2010.03.051","article-title":"Environmental factors in genitourinary development","volume":"184","author":"Yiee","year":"2010","journal-title":"J. Urol."},{"key":"2021042608020090400_DEV119891C56","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.ydbio.2008.04.009","article-title":"An FGF-WNT gene regulatory network controls lung mesenchyme development","volume":"319","author":"Yin","year":"2008","journal-title":"Dev. Biol."},{"key":"2021042608020090400_DEV119891C29","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1242\/jcs.108.1.127","article-title":"Cell-to-cell adherens junction formation and actin filament organization: similarities and differences between non-polarized fibroblasts and polarized epithelial cells","volume":"108","author":"Yonemura","year":"1995","journal-title":"J. Cell Sci."},{"key":"2021042608020090400_DEV119891C57","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1242\/dev.00491","article-title":"Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth","volume":"130","author":"Yu","year":"2003","journal-title":"Development"},{"key":"2021042608020090400_DEV119891C58","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.semcdb.2014.02.016","article-title":"3D in vitro cell culture models of tube formation","volume":"31","author":"Zegers","year":"2014","journal-title":"Semin. Cell Dev. Biol."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/142\/12\/2203\/1693467\/dev119891.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/142\/12\/2203\/1693467\/dev119891.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T12:38:21Z","timestamp":1619440701000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/142\/12\/2203\/46776\/Tissue-specific-roles-of-Fgfr2-in-development-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,15]]},"references-count":58,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2015,6,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.119891","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2015,6,15]]}}}