Molecular Mechanisms of L1-dependnet axon growth (intracellular L2-trafficking and signaling pathways)

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In the developing nervous system, central and peripheral axon tracts are formed by axons that have elongated from the neuronal soma and reached their appropriate targets. Various cell adhesion molecules (CAMs) expressed on the growing axon and its tip (the growth Cone) interact with environmental cues, regulate growth cone motility, and navigate the axon along the correct path. In this research project, we have analyzed the functions of the immunoglobulin superfamily CAM Li and its interacting protein, ankyrin_B, and obtained the following results : 1.Ankyrin_B functions as a molecular clutch that connects retrograde F-actin flow with the L1 cytoplasmic domain (L1CD), thereby transmitting traction force that drives neurite initiation. 2.After moving into the central domain of growth cones by coupling with retrograde F-actin flow, L1 is endocytosed via the AP-2 and clathrin-mediated pathway followed by recycling to the plasma membrane of the growth cone leading edge. This type of intracellular L1 trafficking is required to create and maintain a gradient of L1-mediated adhesion (strong adhesion at the front and weak adhesion at the rear) in growth cones. It is also required for anterograde migration of the growth cones. 3.L1 interaction with AP-2 is regulated by phosphorylation/dephosphorylation of Tyr^<1176> in the L1CD. Clathrin-mediated endocytosis of L1 is triggered by the tyrosine dephosphorylation. 4.This tyrosine can be phosphorylated by the non-receptor tyrosine kinase Src that is localized to lipid rafts, specialized membrane microdomains enriched in cholesterol and sphingolipids. 5.Lipid rafts in the growth cone peripheral domain are critical for L1-based axon growth. These results help to understand the molecular mechanisms of axon growth.