Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation

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.

Automated summary

The Apc protein regulates key effector pathways for tissue homeostasis, with truncating mutations leading to intestinal epithelial tumorigenesis by affecting Wnt pathway and microtubule dynamics. While Wnt pathway plays a role in cell proliferation, Apc also controls epithelial morphology independently of Wnt-responsive Myc-335 element, and disrupts microtubule cytoskeleton without affecting actin cytoskeleton distribution. This study identifies three independent Apc effector pathways in intestinal epithelial regulation: proliferation, microtubule dynamics, and epithelial morphology.