Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats
Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a...
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| Veröffentlicht in: | PloS one 2014-03, Vol.9 (3), p.e91253 |
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| creator | Tuggle, Katherine L Birket, Susan E Cui, Xiaoxia Hong, Jeong Warren, Joe Reid, Lara Chambers, Andre Ji, Diana Gamber, Kevin Chu, Kengyeh K Tearney, Guillermo Tang, Li Ping Fortenberry, James A Du, Ming Cadillac, Joan M Bedwell, David M Rowe, Steven M Sorscher, Eric J Fanucchi, Michelle V |
| description | Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities. |
| doi_str_mv | 10.1371/journal.pone.0091253 |
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Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0091253</identifier><identifier>PMID: 24608905</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Base Sequence ; Biology ; Constipation ; Cystic fibrosis ; Cystic Fibrosis Transmembrane Conductance Regulator - deficiency ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Dentition ; Environmental health ; Epithelium - metabolism ; Female ; Gene Knockout Techniques ; Genetic aspects ; Genetic engineering ; Health sciences ; Hospitals ; Humans ; Ileum - growth & development ; Ileum - physiology ; Ion Channel Gating ; Ion Transport ; Laboratories ; Male ; Medicine ; Membrane Potentials ; Microinjections ; Molecular Sequence Data ; Mucus - metabolism ; Nose - physiology ; Organogenesis ; Pathogenesis ; Pathology ; Public health ; Rats, Sprague-Dawley ; Rodents ; Studies ; Trachea - anatomy & histology ; Trachea - physiology ; Vas Deferens - abnormalities ; Zinc finger proteins</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e91253</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Tuggle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Tuggle et al 2014 Tuggle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-a1ce0785431af0fe340e662d07ebb9091daf7f91d5a81561894d572a3f6142553</citedby><cites>FETCH-LOGICAL-c659t-a1ce0785431af0fe340e662d07ebb9091daf7f91d5a81561894d572a3f6142553</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/PMC3946746/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946746/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24608905$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tuggle, Katherine L</creatorcontrib><creatorcontrib>Birket, Susan E</creatorcontrib><creatorcontrib>Cui, Xiaoxia</creatorcontrib><creatorcontrib>Hong, Jeong</creatorcontrib><creatorcontrib>Warren, Joe</creatorcontrib><creatorcontrib>Reid, Lara</creatorcontrib><creatorcontrib>Chambers, Andre</creatorcontrib><creatorcontrib>Ji, Diana</creatorcontrib><creatorcontrib>Gamber, Kevin</creatorcontrib><creatorcontrib>Chu, Kengyeh K</creatorcontrib><creatorcontrib>Tearney, Guillermo</creatorcontrib><creatorcontrib>Tang, Li Ping</creatorcontrib><creatorcontrib>Fortenberry, James A</creatorcontrib><creatorcontrib>Du, Ming</creatorcontrib><creatorcontrib>Cadillac, Joan M</creatorcontrib><creatorcontrib>Bedwell, David M</creatorcontrib><creatorcontrib>Rowe, Steven M</creatorcontrib><creatorcontrib>Sorscher, Eric J</creatorcontrib><creatorcontrib>Fanucchi, Michelle V</creatorcontrib><title>Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>Biology</subject><subject>Constipation</subject><subject>Cystic fibrosis</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - deficiency</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</subject><subject>Dentition</subject><subject>Environmental health</subject><subject>Epithelium - metabolism</subject><subject>Female</subject><subject>Gene Knockout Techniques</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Health sciences</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Ileum - growth & development</subject><subject>Ileum - 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deficiency</topic><topic>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</topic><topic>Dentition</topic><topic>Environmental health</topic><topic>Epithelium - metabolism</topic><topic>Female</topic><topic>Gene Knockout Techniques</topic><topic>Genetic aspects</topic><topic>Genetic engineering</topic><topic>Health sciences</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Ileum - growth & development</topic><topic>Ileum - physiology</topic><topic>Ion Channel Gating</topic><topic>Ion Transport</topic><topic>Laboratories</topic><topic>Male</topic><topic>Medicine</topic><topic>Membrane Potentials</topic><topic>Microinjections</topic><topic>Molecular Sequence Data</topic><topic>Mucus - metabolism</topic><topic>Nose - physiology</topic><topic>Organogenesis</topic><topic>Pathogenesis</topic><topic>Pathology</topic><topic>Public health</topic><topic>Rats, Sprague-Dawley</topic><topic>Rodents</topic><topic>Studies</topic><topic>Trachea - anatomy & histology</topic><topic>Trachea - 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Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24608905</pmid><doi>10.1371/journal.pone.0091253</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-03, Vol.9 (3), p.e91253 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1504977304 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Base Sequence Biology Constipation Cystic fibrosis Cystic Fibrosis Transmembrane Conductance Regulator - deficiency Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Dentition Environmental health Epithelium - metabolism Female Gene Knockout Techniques Genetic aspects Genetic engineering Health sciences Hospitals Humans Ileum - growth & development Ileum - physiology Ion Channel Gating Ion Transport Laboratories Male Medicine Membrane Potentials Microinjections Molecular Sequence Data Mucus - metabolism Nose - physiology Organogenesis Pathogenesis Pathology Public health Rats, Sprague-Dawley Rodents Studies Trachea - anatomy & histology Trachea - physiology Vas Deferens - abnormalities Zinc finger proteins |
| title | Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T14%3A36%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Characterization%20of%20defects%20in%20ion%20transport%20and%20tissue%20development%20in%20cystic%20fibrosis%20transmembrane%20conductance%20regulator%20(CFTR)-knockout%20rats&rft.jtitle=PloS%20one&rft.au=Tuggle,%20Katherine%20L&rft.date=2014-03-07&rft.volume=9&rft.issue=3&rft.spage=e91253&rft.pages=e91253-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0091253&rft_dat=%3Cgale_plos_%3EA478773365%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1504977304&rft_id=info:pmid/24608905&rft_galeid=A478773365&rft_doaj_id=oai_doaj_org_article_cda01f9339b140bb92a4e09c988812c8&rfr_iscdi=true |