Megaintestine in claudin-15-deficient mice
Megaintestine in claudin-15-deficient mice
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DOI：
10.1053/j.gastro.2007.11.040
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发表时间：
2008-02-01
期刊：
影响因子：
29.4
通讯作者：
Tsukita, Sachiko
中科院分区：
文献类型：
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作者：
Tamura, Atsushi;Kitano, Yuka;Tsukita, Sachiko
背景和目标：紧密连接蛋白（Claudins）是紧密连接（TJ）链的主要组成部分，其形成细胞旁屏障，由24个家族成员组成，其组合决定了基于TJ的细胞旁屏障的性质。在这里，我们产生了claudin-15缺陷（Cldn 15（-/-））小鼠，以检查claudin-15的普遍表达功能。方法：采用常规的基因打靶方法建立Cldn 15（-/-）小鼠模型。由于Cldn 15（-/-）小鼠的小肠上部扩大，我们从组织学、生理学和细胞生物学的各个角度分析了表型。结果：Cldn 15（-/-）小鼠出生后生长发育正常，小肠上部肥大，表现为巨肠。在小肠中，claudin-15的缺乏没有引起其他类型的claudin-1、-2、-3、-4、-7、-12、-18、-20和-23的背景表达的代偿性增加。Cldn 15（-/-）小鼠在没有息肉或癌症等疾病状态的情况下断奶后显示正常隐蔽细胞的增殖增强，导致巨肠，其中小肠上部的长度和直径约为正常的2倍。隐窝中的过渡扩增细胞的数量增加了约2倍。冷冻断裂电子显微镜显示，与Cldn 15（+/+）同窝仔相比，Cldn 15（-/-）空肠远端节段的电导降低，但claudin-15缺乏减少了TJ链的数量。结论：基于在细胞旁屏障形成中没有任何直接作用于细胞增殖的密蛋白的特定作用，如先前在培养的上皮细胞中所示，我们提出基于密蛋白-15的TJ形成以组织包括离子电导的微环境对于小肠的正常大小的形态发生是重要的。
Background & Aims: Claudins, the major components of tight junction (TJ) strands, which form paracellular barriers, consist of 24 family members, the combination of which determines the properties of TJ-based paracellular barriers. Here, we generated claudin-15-deficient (Cldn15(-/-)) mice to examine the ubiquitously expressed functions of claudin-15. Methods: We generated Cldn15(-/-) mice by the conventional gene-targeting strategy. Because the upper small intestine was enlarged in Cldn15(-/-) mice, we analyzed the phenotype from various angles regarding histology, physiology, and cell biology. Results: Cldn15(-/-) mice were born and grew normally with an enlarged upper small intestinal phenotype, megaintestine. Deficiency of claudin-15 did not cause a compensatory increase in the background expression of other types of claudins, claudin-1, -2, -3, -4, -7, -12, -18, -20 and -23, in the small intestine. Cldn15(-/-) mice showed enhanced proliferation of normal cryptic cells after weaning without diseased states such as polyps or cancer, resulting in megaintestine, in which the upper small intestine was approximately 2 times larger than normal in length and diameter. The number of transit-amplifying cells in crypts increased similar to 2-fold. Freeze-fracture electron microscopy revealed that deficiency of claudin-15 decreased the number of TJ strands, although the electric conductance was decreased in distal segments in Cldn15(-/-) jejunum, as compared with Cldn15(+/+) littermates. Conclusions: Based on the specific roles of claudins in paracellular barrier formation without any direct role in cell proliferation, as previously shown in cultured epithelial cells, we propose that claudin-15-based formation of TJs to organize the microenvironment including ion conductance is important for normal-sized morphogenesis of the small intestine.