title: Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats.
abstract: 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.
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tuggle
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Cui
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jeong
authors.initials: J
authors.lastname: Hong
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Warren
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Lara
authors.initials: L
authors.lastname: Reid
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Andre
authors.initials: A
authors.lastname: Chambers
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Ji
authors.affiliation: SAGE Labs, Inc., St. Louis, Missouri, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gamber
authors.affiliation: Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Kengyeh K
authors.initials: KK
authors.lastname: Chu
authors.affiliation: Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Tearney
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Tang
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Fortenberry
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Animal Resources Program, Office of the Vice President for Research, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Du
authors.affiliation: Animal Resources Program, Office of the Vice President for Research, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Cadillac
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Bedwell
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Michelle V
authors.initials: MV
authors.lastname: Fanucchi
mesh_terms: D000818:Animals; D001483:Base Sequence; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000378:metabolism; D003817:Dentition; D004848:Epithelium / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D007082:Ileum / Q000254:growth & development / Q000502:physiology; D015640:Ion Channel Gating; D017136:Ion Transport; D008297:Male; D008564:Membrane Potentials; D008845:Microinjections; D008969:Molecular Sequence Data; D009093:Mucus / Q000378:metabolism; D009666:Nose / Q000502:physiology; D038081:Organogenesis; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000033:anatomy & histology / Q000502:physiology; D014649:Vas Deferens / Q000002:abnormalities
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator