{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:23:57Z","timestamp":1789691037535,"version":"4.0.1"},"reference-count":59,"publisher":"The Company of Biologists","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,12,15]]},"abstract":"<jats:p>During development of the urogenital tract, fibroblast growth factor 8 (Fgf8) is expressed in mesonephric tubules, but its role in this tissue remains undefined. An evaluation of previously generated T-Cre-mediated Fgf8-deficient mice (T-Cre; Fgf8flox\/\u03942,3 mice), which lack Fgf8 expression in the mesoderm, revealed that the cranial region of the Wolffian duct degenerated prematurely and the cranial mesonephric tubules were missing. As a result, the epididymis, vas deferens and efferent ductules were largely absent in mutant mice. Rarb2-Cre was used to eliminate FGF8 from the mesonephric tubules but to allow expression in the adjacent somites. These mutants retained the cranial end of the Wolffian duct and formed the epididymis and vas deferens, but failed to elaborate the efferent ductules, indicating that Fgf8 expression by the mesonephric tubules is required specifically for the formation of the ductules. Ret knockout mice do not form the ureteric bud, a caudal outgrowth of the Wolffian duct and progenitor for the collecting duct network in the kidney, but they do develop the cranial end normally. This indicates that Fgf8, but not Ret, expression is essential to the outgrowth of the cranial mesonephric tubules from the Wolffian duct and to the development of major portions of the sex accessory tissues in the male reproductive tract. Mechanistically, FGF8 functions upstream of Lhx1 expression in forming the nephron, and analysis of Fgf8 mutants similarly shows deficient Lhx1 expression in the mesonephric tubules. These results demonstrate a multifocal requirement for FGF8 in establishing the male reproductive tract ducts and implicate Lhx1 signaling in tubule elongation.<\/jats:p>","DOI":"10.1242\/dev.051888","type":"journal-article","created":{"date-parts":[[2011,11,22]],"date-time":"2011-11-22T13:33:27Z","timestamp":1321968807000},"page":"5369-5378","source":"Crossref","is-referenced-by-count":30,"title":["FGF8 is essential for formation of the ductal system in the male reproductive tract"],"prefix":"10.1242","volume":"138","author":[{"given":"Jirouta","family":"Kitagaki","sequence":"first","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Ueda","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmala","family":"Sharma","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia M.","family":"Elder","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Truffer","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Costantini","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lewandoski","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan O.","family":"Perantoni","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042612363656800_R1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1006\/dbio.1995.0010","article-title":"Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo","volume":"172","author":"Bitgood","year":"1995","journal-title":"Dev. 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Cell"},{"key":"2021042612363656800_R8","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1210\/endo-128-6-2867","article-title":"Androgen receptor expression in developing male reproductive organs","volume":"128","author":"Cooke","year":"1991","journal-title":"Endocrinology"},{"key":"2021042612363656800_R9","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/bies.20357","article-title":"GDNF\/Ret signaling and the development of the kidney","volume":"28","author":"Costantini","year":"2006","journal-title":"BioEssays"},{"key":"2021042612363656800_R10","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00310057","article-title":"Different antigen expression on Wolffian and Mullerian cells in rat embryos as detected by monoclonal antibodies","volume":"176","author":"Dohr","year":"1987","journal-title":"Anat. Embryol."},{"key":"2021042612363656800_R11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0012-1606(03)00250-1","article-title":"FGF-10 plays an essential role in the growth of the fetal prostate","volume":"261","author":"Donjacour","year":"2003","journal-title":"Dev. Biol."},{"key":"2021042612363656800_R12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/dvdy.10205","article-title":"Pronephric duct extension in amphibian embryos: migration and other mechanisms","volume":"226","author":"Drawbridge","year":"2003","journal-title":"Dev. Dyn."},{"key":"2021042612363656800_R13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/(SICI)1520-6408(1999)24:3\/4<263::AID-DVG9>3.0.CO;2-D","article-title":"Perturbation of RET signaling in the embryonic kidney","volume":"24","author":"Ehrenfels","year":"1999","journal-title":"Dev. 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Entwicklungsmech."},{"key":"2021042612363656800_R17","first-page":"737","article-title":"Organogenesis of the mesonephros in birds. Realization in vitro of quail-chicken chimera mesonephros","volume":"272","author":"Gumpel-Pinot","year":"1971","journal-title":"C. R. Acad. Sci. Hebd. Seances Acad. Sci. D"},{"key":"2021042612363656800_R18","first-page":"142","article-title":"Regulation of Wolffian duct development","volume":"67","author":"Hannema","year":"2007","journal-title":"Horm. Res."},{"key":"2021042612363656800_R19","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1002\/jez.1112","article-title":"Wnts and the female reproductive system","volume":"290","author":"Heikkila","year":"2001","journal-title":"J. Exp. Zool."},{"issue":"Suppl.","key":"2021042612363656800_R20","first-page":"47","article-title":"Testicular regulation of epididymal gene expression","volume":"53","author":"Hinton","year":"1998","journal-title":"J. Reprod. 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Biol."},{"key":"2021042612363656800_R39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1677\/erc.0.0070165","article-title":"Fibroblast growth factors, their receptors and signaling","volume":"7","author":"Powers","year":"2000","journal-title":"Endocr. Relat. Cancer"},{"key":"2021042612363656800_R40","first-page":"435","article-title":"Mesonephric kidney \u2013 a stem cell factory?","volume":"43","author":"Sainio","year":"1999","journal-title":"Int. J. Dev. Biol."},{"key":"2021042612363656800_R41","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1242\/dev.124.7.1293","article-title":"Differential regulation of two sets of mesonephric tubules by WT-1","volume":"124","author":"Sainio","year":"1997","journal-title":"Development"},{"key":"2021042612363656800_R42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/382070a0","article-title":"Renal agenesis and the absence of enteric neurons in mice lacking GDNF","volume":"382","author":"Sanchez","year":"1996","journal-title":"Nature"},{"key":"2021042612363656800_R43","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/367380a0","article-title":"Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret","volume":"367","author":"Schuchardt","year":"1994","journal-title":"Nature"},{"key":"2021042612363656800_R44","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1242\/dev.122.6.1919","article-title":"Renal agenesis and hypodysplasia in ret-k-mutant mice result from defects in ureteric bud development","volume":"122","author":"Schuchardt","year":"1996","journal-title":"Development"},{"key":"2021042612363656800_R45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.devcel.2004.11.008","article-title":"The role of GDNF\/Ret signaling in ureteric bud cell fate and branching morphogenesis","volume":"8","author":"Shakya","year":"2005","journal-title":"Dev. 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