Characterization of Defects in Ion Transport and Tissue Development in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Knockout Rats
Katherine L. Tuggle
Susan E. Birket
Xiaoxia Cui
Jeong Hong
Joe Warren
Lara Reid
Andre Chambers
Diana Ji
Kevin Gamber
Kengyeh K. Chu
Guillermo Tearney
Li Ping Tang
James A. Fortenberry
Ming Du
Joan M. Cadillac
David M. Bedwell
Steven M. Rowe
Eric J. Sorscher
Michelle V. Fanucchi
10.1371/journal.pone.0091253
https://plos.figshare.com/articles/dataset/_Characterization_of_Defects_in_Ion_Transport_and_Tissue_Development_in_Cystic_Fibrosis_Transmembrane_Conductance_Regulator_CFTR_Knockout_Rats_/956006
<div><p>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 <i>Cftr</i> gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR<sup>+/−</sup>) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR<sup>−/−</sup>) 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<sup>−/−</sup> rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR<sup>−/−</sup> males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR<sup>−/−</sup> 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.</p></div>
2014-03-07 03:34:38
Anatomy and physiology
Respiratory system
Respiratory physiology
genetics
Human genetics
Autosomal recessive
cystic fibrosis
Model organisms
Animal models
Diagnostic medicine
pathology
anatomical pathology
histopathology
General pathology
molecular pathology
defects
ion
cystic
fibrosis
transmembrane
conductance