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.

A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

“…3F) (Jiménez et al, 2001;Wagner et al, 2003;Páez et al, 2007). The phenomenon of VZ denudation associated with the onset of hydrocephalus has also been found in several mutant mice (Klezovitch et al, 2004;Imai et al, 2006;Ma et al, 2007;Rasin et al, 2007;Nechiporuk et al, 2007). Moreover, in human hydrocephalic fetuses, VZ/ ependymal denudation precedes, and probably triggers the onset of hydrocephalus (Domínguez-Pinos et al, 2005;Sival et al, 2011).…”

“…In brief, abnormal cell junctions of the VZ cells appear as a fi nal common pathway in the alteration of a series of molecules directly or indirectly involved in the assembly of adherens and gap junctions (Chae et al, 2004;Ferland et al, 2009;Sival et al, 2010;Bátiz et al, 2006;Klezovitch et al, 2004;Imai et al, 2006;Ma et al, 2007;Rasin et al, 2007;Nechiporuk et al, 2007). This may explain how a series of diff erent genetic defects aff ecting the VZ/ependyma fi nally leads to its disruption, hydrocephalus and abnormal neurogenesis.…”

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

“…To date, a single mammalian homologue of Scribble (hScrib, Scrb1) has been identified, whereas four Dlgs, Dlg1 (hDlg, SAP97), Dlg2 (Chapsyn-110, PSD-93), Dlg3 (NE-Dlg, SAP102), Dlg4 (PSD-95, SAP90) and two Lgls, Lgl1 and Lgl2 (Hugl1 and 2) have been described (for recent reviews see Humbert et al, 2006;Dow and Humbert, 2007;Assemat et al, 2008;Yamanaka and Ohno, 2008). Dlg5, Dlg6 and Dlg7 are erroneously named and are not members of the Dlg subfamily of membrane-associated guanylate kinases (MAGUKs) (Nechiporuk et al, 2007;te Velthuis et al, 2007, and our unpublished data) and hence will not be referred to further in this review.…”

Ciliary dysfunction in polycystic kidney disease: an emerging model with polarizing potential

“…This reductionist-like approach and its conclusions based on a cellular organelle with unknown functions in the human kidney is risky, because it fails to integrate the data from other studies showing the other cellular localizations and functions for polycystins, protein products of PKD genes (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), as well as other cystic disease proteins (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Furthermore, functional data for proteins in the ciliary plasma membrane is limited.…”