Dysregulation of the epithelial sodium channel (ENaC) occurs in cystic fibrosis, resulting in sodium hyperabsorption in many tissues, including the lungs and the colon. Major phenotypes of cystic fibrosis are due to the resulting defect in surface hydration, including impaired mucociliary clearance and reduced innate immune defense mechanisms (reviewed in Martin, et al., 2018; pubmed:29102290). The human gene implicated in cystic fibrosis is CFTR; this fly model recapitulates downstream effects, not the direct impact of CFTR dysfunction.
In a study characterizing cell renewal in the Drosophila adult midgut, it was found that the fly microRNA mir-263a (mir-bft) downregulates the expression of an ENaC subunit (Nach) in enterocytes. In the absence of mir-263a, multiple phenotypes comparable to those characteristic of cystic fibrosis are observed: the intraluminal surface of the intestine displays dehydration-like phenotypes, sodium levels are increased in enterocytes, stress pathways are activated in enterocytes, and intestinal stem cells overproliferate; mir-263a mutants also have increased bacterial load and expression of antimicrobial peptides.
The Drosophila mir-263a (mir-bft) microRNA exhibits similarity to the human microRNA MIR183. The 3' UTR of Dmel\Nach is predicted to contain multiple mir-263a-binding sites. The 3' UTR of the most closely related human ortholog of Nach, SCNN1G, is predicted to contain multiple MIR183-binding sites.
Pseudomonas aeruginosa, which can cause chronic lung infections in sufferers of cystic fibrosis, has been studied extensively in Drosophila models; see the human disease model report 'Pseudomonas aeruginosa infection' (FBhh0000863).
[updated Mar. 2019 by FlyBase; FBrf0222196]
Cystic fibrosis is caused by homozygous or compound heterozygous mutation in the cystic fibrosis conductance regulator gene (CFTR); this fly model recapitulates downstream effects, not the direct impact of CFTR dysfunction.
The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the distal kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon and some other organs. In the respiratory tract, large segments of the tracts are covered by multi-ciliated cells; ENaC has been shown to be located along the entire length of the cilia. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid. (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=122).
microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. (NCBI Gene, MIR183; 2018.06.21)
The bft/mir-263a 23-nt mature microRNA is similar to the human MIR183 microRNA (FBrf0215696, FBrf0234481).
The bft/mir-263a 23-nt mature microRNA is similar to the human MIR183 microRNA (FBrf0242402, FBrf0234481).
