APC-Mediated Polarity in the Intestinal Stem Cell Niche

The proposed research will determine the mechanisms by which cell and tissue polarity is maintained in the intestinal epithelia. Importantly, inactivation of the tumour suppressor Adenomatous Polyposis Coli (APC) inappropriately activates the Wnt signaling pathway and its oncogenic transcriptional program. This initiates malignant transformation that leads to colorectal cancer. In addition, APC regulates microtubule-based cytoskeletal polarity. Therefore, loss of APC function compromises normal control of cellular proliferation and maintenance of cell polarity, key hallmarks of tumorigenesis. The role of APC-dependent maintenance of cell and tissue polarity in restricting tumorigenesis is a focus of research in my laboratory. Previous studies have established that the APC polarity effector Macf1 is a key determinant of microtubule-based cell polarity. Recent results from my laboratory indicate that Macf1 defines basal polarity in Paneth cells. These cells constitute the intestinal epithelial stem cell niche at the base of the crypts of Lieberkühn where they physically sequester stem cells. We will determine the molecular basis of Macf1 regulation and localization by APC in Paneth cells. We will define how this dictates cellular polarity and the impact on tissue polarity of the intestinal epithelia. We will determine the role of APC in governing cell and tissue polarity by investigating the phenotypic consequences of APC mutation. State-of-the-art organotypic systems, will allow faithful and reproducible modelling of the intestinal epithelium and its malignantly transformed state. This system will be used to elucidate the molecular basis of polarity in Paneth cells and how this impacts on the intestinal epithelium as a whole.