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PMID: 21901156 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.

PloS one ·Vol. 6 ·No. 8 ·2011-00-00 ·Pages e24044

Grieve AG, Daniels RD, Sanchez-Heras E, Hayes MJ, Moss SE, Matter K, Lowe M, Levine TP

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 α-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.

MeSH Terms
Animals Blotting, Western Caco-2 Cells Carrier Proteins/metabolism Cell Line Cell Polarity/genetics,physiology Cell Proliferation Cell Shape/genetics,physiology Dogs Electrophoresis, Polyacrylamide Gel Epithelial Cells/cytology,metabolism Humans Immunoprecipitation Membrane Proteins/metabolism Microscopy, Fluorescence Oculocerebrorenal Syndrome/genetics,metabolism Phosphoproteins/metabolism Phosphoric Monoester Hydrolases/genetics,metabolism RNA Interference Zonula Occludens Proteins Zonula Occludens-1 Protein Zonula Occludens-2 Protein alpha Catenin/metabolism
Chemicals
Carrier Proteins Membrane Proteins Phosphoproteins TJP1 protein, human TJP2 protein, human TJP3 protein, human Zonula Occludens Proteins Zonula Occludens-1 Protein Zonula Occludens-2 Protein alpha Catenin Phosphoric Monoester Hydrolases OCRL protein, human
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Grieve Adam G
Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom.
Daniels Rachel D
Sanchez-Heras Elena
Hayes Matthew J
Moss Stephen E
Matter Karl
Lowe Martin
Levine Timothy P
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0024044
Published
2011-00-00
Epub
2011-00-25
Pages
e24044
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3162020
Subset
IM
Grants
Wellcome Trust · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/H002294/1 · United Kingdom
Wellcome Trust · 084678/78/Z/08/z · United Kingdom
External Links
PubMed source DOI: 10.1371/journal.pone.0024044 PMC Full Text View journal details
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