title: Failure of epithelial tube maintenance causes hydrocephalus and renal cysts in Dlg5-/- mice.
abstract: Epithelial tubes represent fundamental building blocks of metazoan organisms; however, the mechanisms responsible for their formation and maintenance are not well understood. Here, we show that the evolutionarily conserved coiled-coil MAGUK protein Dlg5 is required for epithelial tube maintenance in mammalian brain and kidneys. We demonstrate that Dlg5(-/-) mice develop fully penetrant hydrocephalus and kidney cysts caused by a deficiency in membrane delivery of cadherin-catenin adhesion complexes and loss of cell polarity. Dlg5 travels with cadherin-containing vesicles and binds to syntaxin 4, a t-SNARE protein that regulates fusion of transport vesicles with the lateral membrane domain. We propose that Dlg5 functions in plasma membrane delivery of cadherins by linking cadherin-containing transport vesicles with the t-SNARE targeting complex. These findings show that Dlg5 is causally involved in hydrocephalus and renal cysts and reveal that targeted membrane delivery of cadherin-catenin adhesion complexes is critical for cell polarity and epithelial tube maintenance.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Tamilla
authors.initials: T
authors.lastname: Nechiporuk
authors.forename: Tania E
authors.initials: TE
authors.lastname: Fernandez
authors.forename: Valeri
authors.initials: V
authors.lastname: Vasioukhin
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D004285:Dogs; D018274:Electroporation; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics; D006801:Humans; D006849:Hydrocephalus / Q000209:etiology* / Q000473:pathology; D017403:In Situ Hybridization; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000473:pathology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D008565:Membrane Proteins; D050765:Qa-SNARE Proteins; D051176:beta Catenin; C523873:Dlg5 protein, mouse; D051528:Guanylate Kinases