Amna N. Naser, Tiaosi Xing, Rodney Tatum, Qun Lu, Philip J. Boyer, Yan-Hua Chen
{"title":"结肠隐窝干细胞的功能受紧连接蛋白claudin-7通过Notch/Hippo信号传导的控制","authors":"Amna N. Naser, Tiaosi Xing, Rodney Tatum, Qun Lu, Philip J. Boyer, Yan-Hua Chen","doi":"10.1111/nyas.15137","DOIUrl":null,"url":null,"abstract":"<p>The tight junction protein claudin-7 is essential for tight junction function and intestinal homeostasis. <i>Cldn7</i> 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 <i>Cldn7</i> 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.</p>","PeriodicalId":8250,"journal":{"name":"Annals of the New York Academy of Sciences","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/nyas.15137","citationCount":"0","resultStr":"{\"title\":\"Colonic crypt stem cell functions are controlled by tight junction protein claudin-7 through Notch/Hippo signaling\",\"authors\":\"Amna N. Naser, Tiaosi Xing, Rodney Tatum, Qun Lu, Philip J. Boyer, Yan-Hua Chen\",\"doi\":\"10.1111/nyas.15137\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The tight junction protein claudin-7 is essential for tight junction function and intestinal homeostasis. <i>Cldn7</i> 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 <i>Cldn7</i> 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.</p>\",\"PeriodicalId\":8250,\"journal\":{\"name\":\"Annals of the New York Academy of Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-04-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/nyas.15137\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the New York Academy of Sciences\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/nyas.15137\",\"RegionNum\":3,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the New York Academy of Sciences","FirstCategoryId":"103","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/nyas.15137","RegionNum":3,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Colonic crypt stem cell functions are controlled by tight junction protein claudin-7 through Notch/Hippo signaling
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.
期刊介绍:
Published on behalf of the New York Academy of Sciences, Annals of the New York Academy of Sciences provides multidisciplinary perspectives on research of current scientific interest with far-reaching implications for the wider scientific community and society at large. Each special issue assembles the best thinking of key contributors to a field of investigation at a time when emerging developments offer the promise of new insight. Individually themed, Annals special issues stimulate new ways to think about science by providing a neutral forum for discourse—within and across many institutions and fields.