Analysis of the mechanism of neurite outgrowth driven by membrane transport and cytoskeletal reorganization

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Cytoskeletal reorganization and the membrane addition are pivotal for neurite outgrowth. Here we studied the regulation-mechanism of membrane addition using FRET biosensors. TC10 activity at the plasma membrane decreased at extending growth cones. GTP hydrolysis of TC10 promotes neurite outgrowth through exocytic fusion of Rab11- and L1-containing vesicles by releasing exocyst component Exo70. We developed FRET sensor for Rab35, which promotes neurite outgrowth. Using Rab35 sensor, we showed that Rab35 activity at plasma membrane of growth cones was higher than that of neurite shafts and cell bodies. Phosphorylation of STEF by PKA is critical for Rac1 activation and neurite outgrowth in dbcAMP-treated PC12D cells. We propose that local activation of Rac1 and Cdc42 at neurite tips is necessary for neurite outgrowth. Longest neurite-specific activation of Rap1B in hippocampal neurons contributes to polarity formation through RalA and Nore1A in addition to PI3-kinase.