The adenomatous polyposis coli (Apc) protein regulates diverse effector pathways essential for tissue homeostasis. Truncating oncogenic mutations in Apc removing its Wnt pathway and microtubule regulatory domains drives intestinal epithelia tumorigenesis. Exuberant cell proliferation is one well-established consequence of oncogenic Wnt pathway activity; however, the contribution of other deregulated molecular circuits to tumorigenesis has not been fully examined. Using in vivo and organoid models of intestinal epithelial tumorigenesis we found that Wnt pathway activity controls intestinal epithelial villi and crypt structure, morphological features lost upon Apc inactivation. Although the Wnt pathway target gene c-Myc (also known as Myc) has critical roles in regulating cell proliferation and tumorigenesis, Apc specification of intestinal epithelial morphology is independent of the Wnt-responsive Myc-335 (also known as Rr21) regulatory element. We further demonstrate that Apc inactivation disrupts the microtubule cytoskeleton and consequently localisation of organelles without affecting the distribution of the actin cytoskeleton and associated components. Our data indicates the direct control over microtubule dynamics by Apc through an independent molecular circuit. Our study stratifies three independent Apc effector pathways in the intestinal epithelial controlling: (1) proliferation, (2) microtubule dynamics and (3) epithelial morphology.

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腺瘤性结肠息肉 (Apc) 蛋白调节对组织稳态至关重要的多种效应途径。截断 Apc 中的致癌突变，去除其 Wnt 通路和微管调节结构域，驱动肠上皮细胞肿瘤发生。旺盛的细胞增殖是致癌 Wnt 通路活性的公认结果。然而，其他失调的分子回路对肿瘤发生的贡献尚未得到充分检验。使用肠上皮肿瘤发生的体内和类器官模型，我们发现 Wnt 通路活性控制肠上皮绒毛和隐窝结构，Apc 失活后形态特征丧失。虽然 Wnt 通路靶向基因c-Myc（也称为Myc) 在调节细胞增殖和肿瘤发生中具有关键作用，肠上皮形态的 Apc 规范独立于 Wnt 反应性Myc-335（也称为Rr21）调节元件。我们进一步证明 Apc 失活会破坏微管细胞骨架，从而破坏细胞器的定位，而不影响肌动蛋白细胞骨架和相关成分的分布。我们的数据表明 Apc 通过独立的分子电路直接控制微管动力学。我们的研究对肠上皮控制中的三个独立的 Apc 效应通路进行了分层：（1）增殖，（2）微管动力学和（3）上皮形态。

本文与论文的第一作者进行了相关的第一人称采访。