Collections > Electronic Theses and Dissertations > Adenomatous Polyposis Coli (APC) Regulates Axon Arborizationand Cytoskeleton Organization via its Amino-Terminus

Since its identification in familial adenomatous polyposis, adenomatous polyposis coli (APC) has been extensively studied in cancer biology where it has an established role in the regulation of [beta]-catenin. However, functions of APC related to nervous system development have not been defined. In the first part of my thesis, together with Dr. Anton's group, we demonstrated a remarkable requirement for APC in development of the mouse cerebral cortex. Further, I showed that conditional deletion of APC lead to excessive axonal branching of cortical neurons in vitro. I then investigated the cell biological basis of this neuronal morphological regulation. I have shown that APC is not required for initial polarization of the neuron, but is required for subsequent axon morphological development. Live cell imaging of APC null neurons showed that axons curl during extension and that many supernumerary branches are initiated by growth cone splitting. Examination of the growth cones at early stages of neurite outgrowth shows that both the microtubule and actin cytoskeleton are disorganized as a result of APC deletion. Microtubules are debundled and growth cone lamellipodia are disrupted. Because APC is a multi-domain protein with several motifs with potential to regulate both the microtubule and actin cytoskeleton, I determined which domains of APC are responsible for regulating neuronal morphology. I transfected APC null neurons with specific APC domains fused to GFP. My results indicate that axonal branches do not result from stabilized [beta]-catenin. Further, expression of the C-terminus containing microtubule regulatory domains only partially rescues the branching phenotype. Surprisingly, expression of the N-terminal region of APC completely rescues both the branching and microtubule debundling phenotype. I conclude that APC is required for appropriate regulation of axon morphological development and that the N-terminal region of the protein is the most important domain for regulation of the neuronal cytoskeleton.