The tight junction protein claudin-7 is essential for tight junction function and intestinal homeostasis. Cldn7 deletion in mice leads to an inflammatory bowel disease-like phenotype exhibiting severe intestinal epithelial damage, weight loss, inflammation, mucosal ulcerations, and epithelial hyperplasia. Claudin-7 has also been shown to be involved in cancer metastasis and invasion. Here, we test our hypothesis that claudin-7 plays an important role in regulating colonic intestinal stem cell function. Conditional knockout of Cldn7 in the colon led to impaired epithelial cell differentiation, hyperproliferative epithelium, a decrease in active stem cells, and dramatically altered gene expression profiles. In 3D colonoid culture, claudin-7–deficient crypts were unable to survive and form spheroids, emphasizing the importance of claudin-7 in stem cell survival. Inhibition of the Hippo pathway or activation of Notch signaling partially rescued the defective stem cell behavior. Concurrent Notch activation and Hippo inhibition resulted in restored colonoid survival, growth, and differentiation to the level comparable to those of wild-type derived crypts. In this study, we highlight the essential role of claudin-7 in regulating Notch and Hippo signaling–dependent colonic stem cell functions, including survival, self-renewal, and differentiation. These new findings may shed light on potential avenues to explore for drug development in colorectal cancer.

中文翻译：

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结肠隐窝干细胞功能由紧密连接蛋白claudin-7通过Notch/Hippo信号传导控制


紧密连接蛋白claudin-7 对于紧密连接功能和肠道稳态​​至关重要。小鼠中 Cldn7 缺失会导致炎症性肠病样表型，表现出严重的肠上皮损伤、体重减轻、炎症、粘膜溃疡和上皮增生。 Claudin-7 也被证明参与癌症转移和侵袭。在这里，我们检验了我们的假设，即claudin-7在调节结肠肠干细胞功能中发挥重要作用。结肠中 Cldn7 的条件性敲除导致上皮细胞分化受损、上皮细胞过度增殖、活性干细胞减少以及基因表达谱显着改变。在 3D 类结肠培养中，claudin-7 缺陷的隐窝无法存活并形成球体，这强调了claudin-7 在干细胞存活中的重要性。抑制 Hippo 通路或激活 Notch 信号传导可以部分挽救有缺陷的干细胞行为。同时Notch激活和Hippo抑制导致类集落的存活、生长和分化恢复到与野生型衍生隐窝相当的水平。在这项研究中，我们强调了claudin-7在调节Notch和Hippo信号依赖的结肠干细胞功能（包括生存、自我更新和分化）中的重要作用。这些新发现可能有助于探索结直肠癌药物开发的潜在途径。