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The Journal of Neuroscience, March 2, 2005, 25(9):2181-2191; doi:10.1523/JNEUROSCI.4570-04.2005

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Cellular/Molecular
Trafficking of a Ligand-Receptor Complex on the Growth Cones as an Essential Step for the Uptake of Nerve Growth Factor at the Distal End of the Axon: A Single-Molecule Analysis

Tomomi Tani,¹ Yoshikazu Miyamoto,² Kazuhiro E. Fujimori,³ Takahisa Taguchi,³ Toshio Yanagida,^2,5 Yasushi Sako,^2,4 and Yoshie Harada^1,5

¹Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan, ²Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan, ³Cell Engineering Research Institute, Advanced Industrial Science and Technology, Ikeda 563-8577, Japan, and ⁴Precursory Research for Embryonic Science and Technology, and ⁵Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

The behavior of single molecules of neurotrophins on growth cones was observed by the use of the fluorescent conjugate of nerve growth factor (NGF), Cy3-NGF. After the application of 0.4 nM Cy3-NGF, chick dorsal root ganglion growth cones responded within 1 min of adding the stimulus by expanding their lamellipodia. Only 40 molecules of Cy3-NGF, which occupied <5% of the estimated total binding sites on a single growth cone, were required to initiate the motile responses. After binding to the high-affinity receptor, Cy3-NGF displayed lateral diffusion on the membrane of the growth cones with a diffusion constant of 0.3 µm² s^-1. The behavior of Cy3-NGF was shifted to a one-directional rearward movement toward the central region of the growth cone. The one-directional movement of Cy3-NGF displayed the same rate as the rearward flow of actin, 4 µm/min. This movement could be stopped by the application of the potent inhibitor of actin polymerization, latrunculin B. Molecules of Cy3-NGF were suggested to be internalized in the vicinity of the central region of the growth cone during this rearward trafficking, because Cy3-NGF remained in the growth cone after the growth cones had been exposed to an acidic surrounding medium: acidic medium causes the complete dissociation of Cy3-NGF from the receptors on the surface of growth cones. These results suggested that actin-driven trafficking of the NGF receptor complex is an essential step for the accumulation and endocytosis of NGF at the growth cone and for the retrograde transport of NGF toward the cell body.

Key words: nerve growth factor; growth cone; dorsal root ganglion; fluorescent single-molecule imaging; rearward actin flow; endocytosis

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Received Nov 7, 2004; revised January 5, 2005; accepted January 6, 2005.

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