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Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in...
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Published in: | PloS one 2011-06, Vol.6 (6), p.e21529-e21529 |
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description | Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans. |
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This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021529</identifier><identifier>PMID: 21731775</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Animals, Newborn ; Biochemistry ; Biology ; Budding ; Cancer ; Children ; Chromosome 10 ; Chronic kidney failure ; Cloning ; Congenital anomalies ; Congenital defects ; Conserved Sequence ; Defects ; Drosophila ; Embryo, Mammalian - abnormalities ; Embryo, Mammalian - pathology ; Embryos ; Genes ; Genetic disorders ; Genetic Testing ; Genomes ; Heterozygote ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Insects ; Kidney - abnormalities ; Kidney - embryology ; Kidney - pathology ; Kidney transplantation ; Kidneys ; Ligands ; Medicine ; Mice ; Morphogenesis ; Mutation ; Pax2 protein ; PAX2 Transcription Factor - genetics ; PAX2 Transcription Factor - metabolism ; Pediatric diseases ; Pediatrics ; Protein Binding ; Regulators ; Regulatory Sequences, Nucleic Acid - genetics ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic ; Ureter ; Ureter - abnormalities ; Ureter - embryology ; Ureter - pathology ; Urinary tract ; Urinary Tract - abnormalities ; Urinary Tract - embryology ; Urogenital system ; Vesico-Ureteral Reflux - embryology ; Vesico-Ureteral Reflux - pathology ; Wolffian Ducts - metabolism ; Wolffian Ducts - pathology</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e21529-e21529</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Boualia 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>Boualia et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-8030cadafbf228ef4bc4a91b05abab34f0cbc8807c32a4c7a6c3388dd2fd2db3</citedby><cites>FETCH-LOGICAL-c757t-8030cadafbf228ef4bc4a91b05abab34f0cbc8807c32a4c7a6c3388dd2fd2db3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1312182062/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1312182062?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21731775$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bong Lee, Sean</contributor><creatorcontrib>Boualia, Sami K</creatorcontrib><creatorcontrib>Gaitan, Yaned</creatorcontrib><creatorcontrib>Murawski, Inga</creatorcontrib><creatorcontrib>Nadon, Robert</creatorcontrib><creatorcontrib>Gupta, Indra R</creatorcontrib><creatorcontrib>Bouchard, Maxime</creatorcontrib><title>Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.</description><subject>Analysis</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Budding</subject><subject>Cancer</subject><subject>Children</subject><subject>Chromosome 10</subject><subject>Chronic kidney failure</subject><subject>Cloning</subject><subject>Congenital anomalies</subject><subject>Congenital defects</subject><subject>Conserved Sequence</subject><subject>Defects</subject><subject>Drosophila</subject><subject>Embryo, Mammalian - abnormalities</subject><subject>Embryo, Mammalian - pathology</subject><subject>Embryos</subject><subject>Genes</subject><subject>Genetic disorders</subject><subject>Genetic Testing</subject><subject>Genomes</subject><subject>Heterozygote</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Insects</subject><subject>Kidney - abnormalities</subject><subject>Kidney - embryology</subject><subject>Kidney - pathology</subject><subject>Kidney transplantation</subject><subject>Kidneys</subject><subject>Ligands</subject><subject>Medicine</subject><subject>Mice</subject><subject>Morphogenesis</subject><subject>Mutation</subject><subject>Pax2 protein</subject><subject>PAX2 Transcription Factor - genetics</subject><subject>PAX2 Transcription Factor - metabolism</subject><subject>Pediatric diseases</subject><subject>Pediatrics</subject><subject>Protein Binding</subject><subject>Regulators</subject><subject>Regulatory Sequences, Nucleic Acid - genetics</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>Ureter</subject><subject>Ureter - abnormalities</subject><subject>Ureter - embryology</subject><subject>Ureter - pathology</subject><subject>Urinary tract</subject><subject>Urinary Tract - abnormalities</subject><subject>Urinary Tract - embryology</subject><subject>Urogenital system</subject><subject>Vesico-Ureteral Reflux - embryology</subject><subject>Vesico-Ureteral Reflux - pathology</subject><subject>Wolffian Ducts - metabolism</subject><subject>Wolffian Ducts - pathology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYh_wDxBEQgJx0eKPJHZukKZpQKVJQzDt1jpx7NbFiTs7Qd1-PU6bTQ3aBcpFIud5X9vvOSdJ3mA0x5Thz2vX-xbsfONaNUeI4JyUz5JjXFIyKwiizw--j5KTENYI5ZQXxcvkiGBGMWP5cfL7RgUjo5XqlAebeqVtv02hrVPXrZRPe29a8Hdp50F2aQNWO99AZ1wbUtOmjZEqla7ZuD5KVoOLu79buj6kEUx_wJbszC6aLXmVvNBgg3o9vk-T668X1-ffZ5dX3xbnZ5czyXLWzTiiSEINutKEcKWzSmZQ4grlUEFFM41kJTlHTFICmWRQSEo5r2uia1JX9DR5t7fdWBfEGFMQmGKCOUEFicRiT9QO1mLjTRNvKBwYsVtwfinAd0ZaJUBWGg1REYoyiRFnldQ4x0VWIChRGb2-jLv1VaNqqdqYlJ2YTv-0ZiWW7o-Ix6E0x9Hg42jg3W2vQicaE6SyFloVYxSc5RkveUkj-f4f8unLjdQS4vlNq91QusFTnGWs4LzghEVq_gQVn1rFksaW0iauTwSfJoLIdGrbLaEPQSx-_fx_9upmyn44YFcKbLcKzva7DpuC2R6U3oUQ-_QxY4zEMBEPaYhhIsQ4EVH29rA-j6KHEaB_AboaB_4</recordid><startdate>20110624</startdate><enddate>20110624</enddate><creator>Boualia, Sami K</creator><creator>Gaitan, Yaned</creator><creator>Murawski, Inga</creator><creator>Nadon, Robert</creator><creator>Gupta, Indra R</creator><creator>Bouchard, Maxime</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110624</creationdate><title>Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2</title><author>Boualia, Sami K ; Gaitan, Yaned ; Murawski, Inga ; Nadon, Robert ; Gupta, Indra R ; Bouchard, Maxime</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-8030cadafbf228ef4bc4a91b05abab34f0cbc8807c32a4c7a6c3388dd2fd2db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Biochemistry</topic><topic>Biology</topic><topic>Budding</topic><topic>Cancer</topic><topic>Children</topic><topic>Chromosome 10</topic><topic>Chronic kidney failure</topic><topic>Cloning</topic><topic>Congenital anomalies</topic><topic>Congenital defects</topic><topic>Conserved Sequence</topic><topic>Defects</topic><topic>Drosophila</topic><topic>Embryo, Mammalian - abnormalities</topic><topic>Embryo, Mammalian - pathology</topic><topic>Embryos</topic><topic>Genes</topic><topic>Genetic disorders</topic><topic>Genetic Testing</topic><topic>Genomes</topic><topic>Heterozygote</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Insects</topic><topic>Kidney - abnormalities</topic><topic>Kidney - embryology</topic><topic>Kidney - pathology</topic><topic>Kidney transplantation</topic><topic>Kidneys</topic><topic>Ligands</topic><topic>Medicine</topic><topic>Mice</topic><topic>Morphogenesis</topic><topic>Mutation</topic><topic>Pax2 protein</topic><topic>PAX2 Transcription Factor - genetics</topic><topic>PAX2 Transcription Factor - metabolism</topic><topic>Pediatric diseases</topic><topic>Pediatrics</topic><topic>Protein Binding</topic><topic>Regulators</topic><topic>Regulatory Sequences, Nucleic Acid - genetics</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><topic>Ureter</topic><topic>Ureter - abnormalities</topic><topic>Ureter - embryology</topic><topic>Ureter - pathology</topic><topic>Urinary tract</topic><topic>Urinary Tract - abnormalities</topic><topic>Urinary Tract - embryology</topic><topic>Urogenital system</topic><topic>Vesico-Ureteral Reflux - embryology</topic><topic>Vesico-Ureteral Reflux - pathology</topic><topic>Wolffian Ducts - metabolism</topic><topic>Wolffian Ducts - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boualia, Sami K</creatorcontrib><creatorcontrib>Gaitan, Yaned</creatorcontrib><creatorcontrib>Murawski, Inga</creatorcontrib><creatorcontrib>Nadon, Robert</creatorcontrib><creatorcontrib>Gupta, Indra R</creatorcontrib><creatorcontrib>Bouchard, Maxime</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Science in Context</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 (ProQuest Medical & Health Databases)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (ProQuest Medical & Health Databases)</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)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: 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 - 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This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21731775</pmid><doi>10.1371/journal.pone.0021529</doi><tpages>e21529</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Analysis Animals Animals, Newborn Biochemistry Biology Budding Cancer Children Chromosome 10 Chronic kidney failure Cloning Congenital anomalies Congenital defects Conserved Sequence Defects Drosophila Embryo, Mammalian - abnormalities Embryo, Mammalian - pathology Embryos Genes Genetic disorders Genetic Testing Genomes Heterozygote Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Insects Kidney - abnormalities Kidney - embryology Kidney - pathology Kidney transplantation Kidneys Ligands Medicine Mice Morphogenesis Mutation Pax2 protein PAX2 Transcription Factor - genetics PAX2 Transcription Factor - metabolism Pediatric diseases Pediatrics Protein Binding Regulators Regulatory Sequences, Nucleic Acid - genetics Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic Ureter Ureter - abnormalities Ureter - embryology Ureter - pathology Urinary tract Urinary Tract - abnormalities Urinary Tract - embryology Urogenital system Vesico-Ureteral Reflux - embryology Vesico-Ureteral Reflux - pathology Wolffian Ducts - metabolism Wolffian Ducts - pathology |
title | Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2 |
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