title: Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.
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.
authors: Department of Cell Biology, UCL Institute of Ophthalmology, London, United Kingdom.
authors: Adam G
authors: AG
authors: Grieve
authors: Rachel D
authors: RD
authors: Daniels
authors: Elena
authors: E
authors: Sanchez-Heras
authors: Matthew J
authors: MJ
authors: Hayes
authors: Stephen E
authors: SE
authors: Moss
authors: Karl
authors: K
authors: Matter
authors: Martin
authors: M
authors: Lowe
authors: Timothy P
authors: TP
authors: Levine
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics / Q000502:physiology; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009800:Oculocerebrorenal Syndrome / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D062825:Zonula Occludens Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D051178:alpha Catenin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569046:TJP2 protein, human; C111873:TJP3 protein, human; D062825:Zonula Occludens Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D051178:alpha Catenin; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human