The essential roles of a tumor suppressor Axin in the developing mammalian cerebral cortex

Development of cerebral cortex requires an orchestrated regulation of various developmental processes including neurogenesis, neuronal migration and axon development. While these developmental processes are under tight molecular control, the molecular mechanisms underlying these processes remain largely unclear. My study has elucidated the functional roles of a tumor suppressor protein Axis inhibitor (Axin) in these developmental processes, including regulation of the transition of neural progenitor proliferation to neuronal differentiation, and axon formation. Axin was originally identified as a scaffold protein in the canonical Wnt signaling pathway. I found that Axin regulates neurogenesis through specific interaction with its binding partners in different subcellular compartment of neural progenitors. Interaction of Axin with glycogen synthase kinse 3beta (GSK-3beta) in the cytosolic compartment of cortical neural progenitors is critical for maintaining neural progenitor proliferation. Upon cortical development, Axin is translocated from the cytoplasm to the nucleus of neural progenitors, and triggers neuronal differentiation through its binding with beta-catenin. After neuronal differentiation, Axin was found to be ubiquitously expressed in neurons, with a predominant enrichment along the axons. I demonstrated that Axin is critically required for axon formation and projection during cortex development. Silencing of Axin in neurons abolished the polarized morphology of neurons, and inhibited axon formation in mouse cerebral cortex. Stabilization of microtubule network is sufficient for axon formation. I found that Axin stabilizes the microtubule network through its interaction with GSK-3beta, whose activity is critical for microtubule stability and axon formation.;The subcellular localization and function of Axin is regulated by its phosphorylation. I identified that Axin is an endogenous substrate of cyclin-dependent kinase 5 (Cdk5). Importantly, Cdk5-dependent phosphorylation of Axin mediates the translocation of Axin into the nuclear compartment of neural progenitors, suggesting that Axin phosphorylation is important for regulating the transition from proliferation to differentiation during neurogenesis. Cdk5-mediated phosphorylation of Axin is also important for axon formation in cerebral cortical neurons, through enhancing the interaction of Axin with GSK-3beta, thereby stabilizing the microtubule network. Together, my study uncovers the novel roles of Axin in neurogenesis and axon formation during cerebral cortex development, and underscores the functional significance of Cdk5-Axin-GSK-3beta signaling in the developmental processes.