title: Defective CFTR apical endocytosis and enterocyte brush border in myosin VI-deficient mice.
abstract: In polarized epithelial cells such as those that line the inner ear, kidney and gut, myosin VI has been localized to the intermicrovillar domains where it is proposed to regulate clathrin-dependent endocytosis; however, a direct role for myosin VI in apical endocytosis has not been shown. We examined the apical membrane distribution and endocytosis of cystic fibrosis transmembrane conductance regulator (CFTR) in myosin VI-deficient Snell's Waltzer Myo6((sv/sv)) mice. Confocal microscopy and cell-surface biotinylation confirmed that surface levels of CFTR in the intestine of Myo6((sv/sv)) mice were markedly higher, and CFTR internalization from the apical plasma membrane was reduced compared with heterozygous controls. Consistent with a defect in CFTR endocytosis and accumulation at the cell surface, exaggerated CFTR-mediated fluid secretion was observed in Myo6((sv/sv)) mice following treatment of isolated jejunum with the cyclic GMP-activated heat stable enterotoxin. These data establish that myosin VI modulates apical endocytosis and may be an important physiological modulator of CFTR function and CFTR-associated secretory diarrhea in the gut.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. nameen@pitt.edu
authors.forename: Nadia
authors.initials: N
authors.lastname: Ameen
authors.forename: Gerard
authors.initials: G
authors.lastname: Apodaca
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D020895:Enterocytes / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000473:pathology; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics*
chemical_list: C089785:myosin VI; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D018995:Myosin Heavy Chains