An experimental and mathematical analysis of nerve growth cone motility based on cytoskeletal actin dynamics.

摘要

During development and regeneration, nerve growth cones, in response to their environment, control the rate and direction of neurite outgrowth. Dynamic changes in the structure of the underlying cytoskeleton have been implicated in the outgrowth process, and the cytoskeletal protein actin is thought to be of primary importance. Polymerization of actin filaments leading to extension of lamellipodia and filopodia, retrograde translocation of actin filaments, and interactions with the substratum all combine to move the growth cone towards its appropriate target. To provide a quantitative and mechanistic basis for determining the contribution of cytoskeletal actin in growth cone movement, a model describing actin dynamics within the growth cone was developed.; The model accounts for actin polymerization and flow, as well as forces thought to affect growth cone movement. Actin polymerization at the leading front of the growth cone is assumed to be responsible for protrusion while a constant retrograde force acting throughout the growth cone results in rearward flow of polymer. The balance between polymerization and retrograde flow results in motility. In addition, environmental factors are incorporated into the model in the form of interactions with the substrate, which are believed to modify motility.; Shape and movement characteristics from growth cone simulations were compared to those of chick dorsal root ganglia growth cones using time series analyses such as the mean value, root mean square error, and the autocorrelation function. In addition to observing similar behaviors for experimental growth cones in terms of movement parameters, root mean square analysis showed that the simulation results describe all growth cone shape and movement parameters measured to within an order of magnitude agreement, while the mean value analysis showed that intermediate values of substrate attachment are closest in agreement to those of experiment. The autocorrelation functions of simulated growth cone turn angles show a pattern of behavior similar to that of experimental growth cones. These results show that growth cone behavior, while highly dynamic, demonstrates a similar type of behavior for movement parameters for different growth cones. The model simulation results lend insight into possible mechanisms of actin contribution to growth cone motility.