Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.
Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.
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DOI：
10.1371/journal.pone.0024044
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Levine TP
中科院分区：
文献类型：
--
作者：
Grieve AG;Daniels RD;Sanchez-Heras E;Hayes MJ;Moss SE;Matter K;Lowe M;Levine TP
肌醇多磷酸5-磷酸酶OCRL 1的突变会导致劳氏综合征，导致白内障、智力迟钝和肾衰竭。我们注意到Lowe综合征中受影响的细胞类型是高度极化的，因此我们研究了上皮细胞中的OCRL 1，因为它们从孤立的单个细胞成熟为极化的片层和囊肿，相邻细胞之间有广泛的交流。我们发现，一部分OCRL 1的目标细胞间连接在其形成的早期阶段，共定位与adherens连接组件和紧密连接组件。与这种分布相关，OCRL 1与连接组分α-连环蛋白和闭合小带（ZO）-1/2/3形成复合物。生长为片状的上皮细胞中OCRL 1的耗尽会抑制成熟;细胞保持扁平，无法极化顶端标记物，并且还表现出增殖减少。对形状的影响通过重新表达的OCRL 1恢复，并且需要5′-磷酸酶结构域，表明5-磷酸化肌醇的下调对于上皮发育是必要的。OCRL 1在上皮成熟中的作用在三维培养中更强烈，其中缺乏OCRL 1的上皮细胞不仅不能形成中央腔，而且也没有ZO-1的正确细胞内分布，这表明当细胞作为囊肿生长时，OCRL 1在细胞间连接成熟的早期起作用。OCRL 1在极化细胞连接中的作用可以解释Lowe综合征中受影响器官的模式。
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.
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影响因子：
11.4
作者：
HANZEL, D;REGGIO, H;MANGEAT, P
通讯作者：
MANGEAT, P
影响因子：
3.6
作者：
Hellsten, E;Bernard, DJ;Nussbaum, RL
通讯作者：
Nussbaum, RL
通过表达突变型紧密连接膜蛋白，细胞旁通透性和跨上皮电阻的功能性分离以及顶端-基底外侧膜内扩散屏障的破坏。
影响因子：
7.8
作者：
Balda, M S;Whitney, J A;Flores, C;Gonzalez, S;Cereijido, M;Matter, K
通讯作者：
Matter, K
影响因子：
7.8
作者：
Devaux, Jerome;Gow, Alexander
通讯作者：
Gow, Alexander
影响因子：
4
作者：
Horikoshi, Yosuke;Suzuki, Atsushi;Ohno, Shigeo
通讯作者：
Ohno, Shigeo