Hdl Handle:
http://hdl.handle.net/10675.2/755
Title:
Lowe Syndrome Protein OCRL1 Supports Maturation of Polarized Epithelial Cells
Authors:
Grieve, Adam G.; Daniels, Rachel D.; Sanchez-Heras, Elena; Hayes, Matthew J. ( 0000-0003-1651-0956 ) ; Moss, Stephen E.; Matter, Karl; Lowe, Martin; Levine, Timothy P.
Abstract:
Mutations in the inositol polyphosphate 5-phosphatase OCRL1 cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure. We noted that cell types affected in Lowe Syndrome are highly polarized, and therefore we studied OCRL1 in epithelial cells as they mature from isolated individual cells into polarized sheets and cysts with extensive communication between neighbouring cells. We show that a proportion of OCRL1 targets intercellular junctions at the early stages of their formation, co-localizing both with adherens junctional components and with tight junctional components. Correlating with this distribution, OCRL1 forms complexes with junctional components a-catenin and zonula occludens (ZO)-1/2/3. Depletion of OCRL1 in epithelial cells growing as a sheet inhibits maturation; cells remain flat, fail to polarize apical markers and also show reduced proliferation. The effect on shape is reverted by re-expressed OCRL1 and requires the 5'-phosphatase domain, indicating that down-regulation of 5-phosphorylated inositides is necessary for epithelial development. The effect of OCRL1 in epithelial maturation is seen more strongly in 3-dimensional cultures, where epithelial cells lacking OCRL1 not only fail to form a central lumen, but also do not have the correct intracellular distribution of ZO-1, suggesting that OCRL1 functions early in the maturation of intercellular junctions when cells grow as cysts. A role of OCRL1 in junctions of polarized cells may explain the pattern of organs affected in Lowe Syndrome.
Citation:
PLoS One. 2011 Aug 25; 6(8):e24044
Issue Date:
25-Aug-2011
URI:
http://hdl.handle.net/10675.2/755
DOI:
10.1371/journal.pone.0024044
PubMed ID:
21901156
PubMed Central ID:
PMC3162020
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorGrieve, Adam G.en_US
dc.contributor.authorDaniels, Rachel D.en_US
dc.contributor.authorSanchez-Heras, Elenaen_US
dc.contributor.authorHayes, Matthew J.en_US
dc.contributor.authorMoss, Stephen E.en_US
dc.contributor.authorMatter, Karlen_US
dc.contributor.authorLowe, Martinen_US
dc.contributor.authorLevine, Timothy P.en_US
dc.date.accessioned2012-10-26T20:28:40Z-
dc.date.available2012-10-26T20:28:40Z-
dc.date.issued2011-08-25en_US
dc.identifier.citationPLoS One. 2011 Aug 25; 6(8):e24044en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21901156en_US
dc.identifier.doi10.1371/journal.pone.0024044en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/755-
dc.description.abstractMutations in the inositol polyphosphate 5-phosphatase OCRL1 cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure. We noted that cell types affected in Lowe Syndrome are highly polarized, and therefore we studied OCRL1 in epithelial cells as they mature from isolated individual cells into polarized sheets and cysts with extensive communication between neighbouring cells. We show that a proportion of OCRL1 targets intercellular junctions at the early stages of their formation, co-localizing both with adherens junctional components and with tight junctional components. Correlating with this distribution, OCRL1 forms complexes with junctional components a-catenin and zonula occludens (ZO)-1/2/3. Depletion of OCRL1 in epithelial cells growing as a sheet inhibits maturation; cells remain flat, fail to polarize apical markers and also show reduced proliferation. The effect on shape is reverted by re-expressed OCRL1 and requires the 5'-phosphatase domain, indicating that down-regulation of 5-phosphorylated inositides is necessary for epithelial development. The effect of OCRL1 in epithelial maturation is seen more strongly in 3-dimensional cultures, where epithelial cells lacking OCRL1 not only fail to form a central lumen, but also do not have the correct intracellular distribution of ZO-1, suggesting that OCRL1 functions early in the maturation of intercellular junctions when cells grow as cysts. A role of OCRL1 in junctions of polarized cells may explain the pattern of organs affected in Lowe Syndrome.en_US
dc.rightsGrieve et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectEnzymesen_US
dc.subjectEnzyme Regulationen_US
dc.subjectLipidsen_US
dc.subjectLipid Metabolismen_US
dc.subjectMetabolismen_US
dc.subjectLipid Metabolismen_US
dc.subjectProteinsen_US
dc.subjectProtein Interactionsen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectCellular Structuresen_US
dc.subjectSubcellular Organellesen_US
dc.subjectMembranes and Sortingen_US
dc.titleLowe Syndrome Protein OCRL1 Supports Maturation of Polarized Epithelial Cellsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3162020en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

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