Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux
Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolff...
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| description | Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity.
We conditionally deleted Fgfr2 in ST (Fgfr2(ST-/-)) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects.
We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2(ST-/-) mice at embryonic day (E) 10.5. E11.5 Fgfr2(ST-/-) mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2(ST-/-) mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2(ST-/-) mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes.
Mutations in FGFR2 could possibly cause VUR in humans. |
| doi_str_mv | 10.1371/journal.pone.0056062 |
| format | Article |
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We conditionally deleted Fgfr2 in ST (Fgfr2(ST-/-)) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects.
We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2(ST-/-) mice at embryonic day (E) 10.5. E11.5 Fgfr2(ST-/-) mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2(ST-/-) mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2(ST-/-) mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes.
Mutations in FGFR2 could possibly cause VUR in humans.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0056062</identifier><identifier>PMID: 23409123</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abnormalities ; Animal tissues ; Animals ; Apoptosis ; Biology ; Bladder ; Bone Morphogenetic Protein 4 - genetics ; Bone Morphogenetic Protein 4 - metabolism ; Bone morphogenetic proteins ; Children & youth ; Defects ; Embryos ; Fibroblast growth factor ; Fibroblast growth factor receptor 2 ; Fibroblast growth factors ; Fibroblasts ; Flow cytometry ; Gene Deletion ; Gene expression ; Gene Expression Regulation, Developmental ; Growth factors ; Histology ; Hospitals ; Hypoplasia ; Insertion ; Kidneys ; Mathematics ; Medicine ; Mesenchyme ; Mice ; Mice, Knockout ; Morphogenesis ; mRNA ; Mutants ; Mutation ; Nephrology ; Pediatrics ; Proteins ; Receptor, Fibroblast Growth Factor, Type 2 - genetics ; RNA ; Stem cells ; Stroma ; Stromal Cells - metabolism ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; Ureter ; Ureter - abnormalities ; Ureter - embryology ; Urinary bladder ; Urinary Bladder - abnormalities ; Urinary Bladder - embryology ; Urinary tract ; Urogenital Abnormalities - embryology ; Urogenital Abnormalities - genetics ; Urogenital system ; Vesico-Ureteral Reflux - genetics ; Wolffian Ducts - metabolism</subject><ispartof>PloS one, 2013-02, Vol.8 (2), p.e56062</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Walker et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Walker et al 2013 Walker et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-e4969a82961af8c5ed635e7e92ae3a3e21d4fcb5fd953435609b28aca07afda73</citedby><cites>FETCH-LOGICAL-c758t-e4969a82961af8c5ed635e7e92ae3a3e21d4fcb5fd953435609b28aca07afda73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567073/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567073/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23409123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yue, Junming</contributor><creatorcontrib>Walker, Kenneth A</creatorcontrib><creatorcontrib>Sims-Lucas, Sunder</creatorcontrib><creatorcontrib>Di Giovanni, Valeria E</creatorcontrib><creatorcontrib>Schaefer, Caitlin</creatorcontrib><creatorcontrib>Sunseri, Whitney M</creatorcontrib><creatorcontrib>Novitskaya, Tatiana</creatorcontrib><creatorcontrib>de Caestecker, Mark P</creatorcontrib><creatorcontrib>Chen, Feng</creatorcontrib><creatorcontrib>Bates, Carlton M</creatorcontrib><title>Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity.
We conditionally deleted Fgfr2 in ST (Fgfr2(ST-/-)) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects.
We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2(ST-/-) mice at embryonic day (E) 10.5. E11.5 Fgfr2(ST-/-) mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2(ST-/-) mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2(ST-/-) mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes.
Mutations in FGFR2 could possibly cause VUR in humans.</description><subject>Abnormalities</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Bladder</subject><subject>Bone Morphogenetic Protein 4 - genetics</subject><subject>Bone Morphogenetic Protein 4 - metabolism</subject><subject>Bone morphogenetic proteins</subject><subject>Children & youth</subject><subject>Defects</subject><subject>Embryos</subject><subject>Fibroblast growth factor</subject><subject>Fibroblast growth factor receptor 2</subject><subject>Fibroblast growth factors</subject><subject>Fibroblasts</subject><subject>Flow cytometry</subject><subject>Gene Deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Growth factors</subject><subject>Histology</subject><subject>Hospitals</subject><subject>Hypoplasia</subject><subject>Insertion</subject><subject>Kidneys</subject><subject>Mathematics</subject><subject>Medicine</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Morphogenesis</subject><subject>mRNA</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Nephrology</subject><subject>Pediatrics</subject><subject>Proteins</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - genetics</subject><subject>RNA</subject><subject>Stem cells</subject><subject>Stroma</subject><subject>Stromal Cells - metabolism</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>Ureter</subject><subject>Ureter - abnormalities</subject><subject>Ureter - embryology</subject><subject>Urinary bladder</subject><subject>Urinary Bladder - abnormalities</subject><subject>Urinary Bladder - embryology</subject><subject>Urinary tract</subject><subject>Urogenital Abnormalities - embryology</subject><subject>Urogenital Abnormalities - genetics</subject><subject>Urogenital system</subject><subject>Vesico-Ureteral Reflux - genetics</subject><subject>Wolffian Ducts - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAQhk1padJt36C0gkKhF7uVJduybwohPS0EAj3dirE82tWitTaSnKQv0uet3HXCLrRQfCGh-eaf0W9Nlj3P6SLnIn-7cYPvwS52rscFpWVFK_YgO80bzuYVo_zhwf4kexLCJkG8rqrH2QnjBW1yxk-zX-_RYjSuJ04TbVrvWgshkpV3N3FNNKjoPPGocDduGNHebUlcI9mhN_MbZ7U20JNuUJGEmIJALEIXSHRk8BgTpYjpx_hYBdre-S1YEw0GAn1HrjEY5fYo2FRK2-H2afZIgw34bFpn2fePH76df55fXH5anp9dzJUo6zjHoqkaqFlT5aBrVWJX8RIFNgyQA0eWd4VWbam7puQFTx41LatBARWgOxB8lr3c6-6sC3KyNMicc1qLuk7rLFvuic7BRu682YL_KR0Y-efA-ZUEH42yKJngvNIUBONQABdNW-YVazqei4Z3NSatd1O1od1ip7CP6cpHoseR3qzlyl3L1LmgYmzm1STg3dWAIf6j5YlaQerK9NolMbU1QcmzQtQFzVlDE7X4C5W-Drfph_SoTTo_SnhzlJCYiLdxBUMIcvn1y_-zlz-O2dcH7BrBxnVwdhjfSzgGiz2ovAshPZR753Iqx5m4c0OOMyGnmUhpLw5dv0-6GwL-GwOUCic</recordid><startdate>20130207</startdate><enddate>20130207</enddate><creator>Walker, Kenneth A</creator><creator>Sims-Lucas, Sunder</creator><creator>Di Giovanni, Valeria E</creator><creator>Schaefer, Caitlin</creator><creator>Sunseri, Whitney M</creator><creator>Novitskaya, Tatiana</creator><creator>de Caestecker, Mark P</creator><creator>Chen, Feng</creator><creator>Bates, Carlton M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130207</creationdate><title>Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux</title><author>Walker, Kenneth A ; Sims-Lucas, Sunder ; Di Giovanni, Valeria E ; Schaefer, Caitlin ; Sunseri, Whitney M ; Novitskaya, Tatiana ; de Caestecker, Mark P ; Chen, Feng ; Bates, Carlton M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-e4969a82961af8c5ed635e7e92ae3a3e21d4fcb5fd953435609b28aca07afda73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Abnormalities</topic><topic>Animal tissues</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Bladder</topic><topic>Bone Morphogenetic Protein 4 - 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metabolism</topic><topic>T-Box Domain Proteins - genetics</topic><topic>T-Box Domain Proteins - metabolism</topic><topic>Ureter</topic><topic>Ureter - abnormalities</topic><topic>Ureter - embryology</topic><topic>Urinary bladder</topic><topic>Urinary Bladder - abnormalities</topic><topic>Urinary Bladder - embryology</topic><topic>Urinary tract</topic><topic>Urogenital Abnormalities - embryology</topic><topic>Urogenital Abnormalities - genetics</topic><topic>Urogenital system</topic><topic>Vesico-Ureteral Reflux - genetics</topic><topic>Wolffian Ducts - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Walker, Kenneth A</creatorcontrib><creatorcontrib>Sims-Lucas, Sunder</creatorcontrib><creatorcontrib>Di Giovanni, Valeria E</creatorcontrib><creatorcontrib>Schaefer, Caitlin</creatorcontrib><creatorcontrib>Sunseri, Whitney M</creatorcontrib><creatorcontrib>Novitskaya, Tatiana</creatorcontrib><creatorcontrib>de Caestecker, Mark P</creatorcontrib><creatorcontrib>Chen, Feng</creatorcontrib><creatorcontrib>Bates, Carlton M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Walker, Kenneth A</au><au>Sims-Lucas, Sunder</au><au>Di Giovanni, Valeria E</au><au>Schaefer, Caitlin</au><au>Sunseri, Whitney M</au><au>Novitskaya, Tatiana</au><au>de Caestecker, Mark P</au><au>Chen, Feng</au><au>Bates, Carlton M</au><au>Yue, Junming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-02-07</date><risdate>2013</risdate><volume>8</volume><issue>2</issue><spage>e56062</spage><pages>e56062-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity.
We conditionally deleted Fgfr2 in ST (Fgfr2(ST-/-)) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects.
We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2(ST-/-) mice at embryonic day (E) 10.5. E11.5 Fgfr2(ST-/-) mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2(ST-/-) mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2(ST-/-) mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes.
Mutations in FGFR2 could possibly cause VUR in humans.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23409123</pmid><doi>10.1371/journal.pone.0056062</doi><tpages>e56062</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-02, Vol.8 (2), p.e56062 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1330878813 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Abnormalities Animal tissues Animals Apoptosis Biology Bladder Bone Morphogenetic Protein 4 - genetics Bone Morphogenetic Protein 4 - metabolism Bone morphogenetic proteins Children & youth Defects Embryos Fibroblast growth factor Fibroblast growth factor receptor 2 Fibroblast growth factors Fibroblasts Flow cytometry Gene Deletion Gene expression Gene Expression Regulation, Developmental Growth factors Histology Hospitals Hypoplasia Insertion Kidneys Mathematics Medicine Mesenchyme Mice Mice, Knockout Morphogenesis mRNA Mutants Mutation Nephrology Pediatrics Proteins Receptor, Fibroblast Growth Factor, Type 2 - genetics RNA Stem cells Stroma Stromal Cells - metabolism T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism Ureter Ureter - abnormalities Ureter - embryology Urinary bladder Urinary Bladder - abnormalities Urinary Bladder - embryology Urinary tract Urogenital Abnormalities - embryology Urogenital Abnormalities - genetics Urogenital system Vesico-Ureteral Reflux - genetics Wolffian Ducts - metabolism |
| title | Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux |
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