N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation
N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation
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DOI：
10.1242/dev.048488
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发表时间：
2010-07-15
期刊：
影响因子：
4.6
通讯作者：
Kemler, Rolf
中科院分区：
文献类型：
--
作者：
Libusova, Lenka;Stemmler, Marc P.;Kemler, Rolf
我们有条件地取代E-钙粘蛋白（E-cad;钙粘蛋白1）与N-钙粘蛋白（N-cad;钙粘蛋白2）在肠道发育过程中产生的小鼠，其中Ncad cDNA敲入Ecad基因座。突变小鼠出生，证明N-cad可以在结构上取代E-cad并建立适当的器官结构。出生后，突变小鼠在小肠和大肠中逐渐发展出突变表型，并在近似2-3周龄时死亡，可能是由于过渡到固体食物期间的营养不良。分子分析揭示了从隐窝到绒毛区域的细胞扩展域，β-连环蛋白（β-cat; Ctnnb 1）的核定位和几个β-cat靶基因的表达增强。此外，BMP信号通路在绒毛的肠上皮中被抑制，表明N-cad可能干扰肠上皮细胞层中的BMP信号。有趣的是，突变小鼠出现了严重的发育异常，并且具有肿瘤特征的细胞簇沿着小肠和大肠中的隐窝-绒毛轴分散。我们的实验模型表明，在E-cad的情况下，N-cad在上皮环境中的唯一表达足以诱导肿瘤转化。
We conditionally substituted E-cadherin (E-cad; cadherin 1) with N-cadherin (N-cad; cadherin 2) during intestine development by generating mice in which an Ncad cDNA was knocked into the Ecad locus. Mutant mice were born, demonstrating that N-cad can structurally replace E-cad and establish proper organ architecture. After birth, mutant mice gradually developed a mutant phenotype in both the small and large intestine and died at similar to 2-3 weeks of age, probably due to malnutrition during the transition to solid food. Molecular analysis revealed an extended domain of cells from the crypt into the villus region, with nuclear localization of beta-catenin (beta-cat; Ctnnb1) and enhanced expression of several beta-cat target genes. In addition, the BMP signaling pathway was suppressed in the intestinal epithelium of the villi, suggesting that N-cad might interfere with BMP signaling in the intestinal epithelial cell layer. Interestingly, mutant mice developed severe dysplasia and clusters of cells with neoplastic features scattered along the crypt-villus axis in the small and large intestine. Our experimental model indicates that, in the absence of E-cad, the sole expression of N-cad in an epithelial environment is sufficient to induce neoplastic transformations.