The formation of functional neural networks requires precise regulation of the growth and branching of the terminal arbors of axons, processes known to be influenced by early network electrical activity1,2,3. Here we show that a rule of activity-based competition between neighbouring axons appears to govern the growth and branching of retinal ganglion cell (RGC) axon arbors in the developing optic tectum of zebrafish. Mosaic expression of an exogenous potassium channel or a dominant-negative SNARE protein was used to suppress electrical or neurosecretory activity in subsets of RGC axons. Imaging in vivo showed that these forms of activity suppression strongly inhibit both net growth and the formation of new branches by individually transfected RGC axon arbors. The inhibition is relieved when the activity of nearby ‘competing’ RGC axons is also suppressed. These results therefore identify a new form of activity-based competition rule that might be a key regulator of axon growth and branch initiation.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sanes, J. R. & Lichtman, J. W. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442 (1999)
Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996)
Zhang, L. I. & Poo, M. M. Electrical activity and development of neural circuits. Nature Neurosci. 4 (Suppl), 1207–1214 (2001)
Buffelli, M. et al. Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition. Nature 424, 430–434 (2003)
Lichtman, J. W. & Balice-Gordon, R. J. Understanding synaptic competition in theory and in practice. J. Neurobiol. 21, 99–106 (1990)
Shatz, C. J. & Stryker, M. P. Ocular dominance in layer IV of the cat's visual cortex and the effects of monocular deprivation. J. Physiol. (Lond.) 281, 267–283 (1978)
Stryker, M. P. & Harris, W. A. Binocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex. J. Neurosci. 6, 2117–2133 (1986)
Antonini, A. & Stryker, M. P. Rapid remodeling of axonal arbors in the visual cortex. Science 260, 1819–1821 (1993)
Yu, C. R. et al. Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map. Neuron 42, 553–566 (2004)
Zhao, H. & Reed, R. R. X inactivation of the OCNC1 channel gene reveals a role for activity-dependent competition in the olfactory system. Cell 104, 651–660 (2001)
Ruthazer, E. S., Akerman, C. J. & Cline, H. T. Control of axon branch dynamics by correlated activity in vivo . Science 301, 66–70 (2003)
Schmidt, J. T., Buzzard, M., Borress, R. & Dhillon, S. MK801 increases retinotectal arbor size in developing zebrafish without affecting kinetics of branch elimination and addition. J. Neurobiol. 42, 303–314 (2000)
Schmidt, J. T., Fleming, M. R. & Leu, B. Presynaptic protein kinase C controls maturation and branch dynamics of developing retinotectal arbors: possible role in activity-driven sharpening. J. Neurobiol. 58, 328–340 (2004)
Gnuegge, L., Schmid, S. & Neuhauss, S. C. Analysis of the activity-deprived zebrafish mutant macho reveals an essential requirement of neuronal activity for the development of a fine-grained visuotopic map. J. Neurosci. 21, 3542–3548 (2001)
Johnson, F. A., Dawson, A. J. & Meyer, R. L. Activity-dependent refinement in the goldfish retinotectal system is mediated by the dynamic regulation of processes withdrawal: an in vivo imaging study. J. Comp. Neurol. 406, 548–562 (1999)
Burrone, J., O'Byrne, M. & Murthy, V. N. Multiple forms of synaptic plasticity triggered by selective suppression of activity in individual neurons. Nature 420, 414–418 (2002)
Drapeau, P. et al. Development of the locomotor network in zebrafish. Prog. Neurobiol. 68, 85–111 (2002)
Koster, R. W. & Fraser, S. E. Tracing transgene expression in living zebrafish embryos. Dev. Biol. 233, 329–346 (2001)
Sorensen, J. B. et al. The SNARE protein SNAP-25 is linked to fast calcium triggering of exocytosis. Proc. Natl Acad. Sci. USA 99, 1627–1632 (2002)
Li, W., Ono, F. & Brehm, P. Optical measurements of presynaptic release in mutant zebrafish lacking postsynaptic receptors. J. Neurosci. 23, 10467–10474 (2003)
Scales, S. J. et al. SNAREs contribute to the specificity of membrane fusion. Neuron 26, 457–464 (2000)
Hua, J. Y. & Smith, S. J. Neural activity and the dynamics of central nervous system development. Nature Neurosci. 7, 327–332 (2004)
Cogen, J. & Cohen-Cory, S. Nitric oxide modulates retinal ganglion cell axon arbor remodeling in vivo . J. Neurobiol. 45, 120–133 (2000)
Cohen-Cory, S. & Fraser, S. E. Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo . Nature 378, 192–196 (1995)
Haas, K., Jensen, K., Sin, W. C., Foa, L. & Cline, H. T. Targeted electroporation in Xenopus tadpoles in vivo—from single cells to the entire brain. Differentiation 70, 148–154 (2002)
We thank T. R. Clandinin, R. W. Tsien, R. W. Aldrich, L. Luo and the Smith laboratory for comments on the manuscript, and C. M. Niell for developing the Matlab routines used in image analysis. We thank T. Roeser for isolating the brn3c promoter. The US National Institutes of Health and the Vincent Coates Foundation provided financial support. J.Y.H. was supported by a Stanford Graduate Fellowship and a Coates Foundation Fellowship. M.C.S. was supported by a predoctoral fellowship from the American Heart Association.
The authors declare that they have no competing financial interests.
This document contains Supplementary Figure S1 and accompanying legend. The figure shows that Kir2.1 and VAMP-GFP coexpress with high efficiency. (DOC 406 kb)
This movie shows the growth of a VAMP-GFP expressing RGC axon arbor. Images were collected at two-minute intervals for 48 minutes. Scale bars represent 5µm in all movies. Auto-fluorescence of the skin is seen in the upper left corner of this movie and in some of the other movies presented (QuickTime; 5MB). (MOV 517 kb)
This movie shows the growth of a Kir2.1 and VAMP-GFP expressing RGC axon arbor. Images were collected at two-minute intervals for 48 minutes. The axon shows less exploratory behaviour compared with control axons expressing VAMP-GFP (Supplementary movie 1). (MOV 514 kb)
This movie shows the growth of a VAMPm expressing RGC axon arbor. Images were collected at two-minute intervals for 48 minutes. The axon shows less exploratory behaviour compared with control axons expressing VAMP-GFP (Supplementary movie 1). (MOV 707 kb)
This movie shows the growth of a VAMP-GFP expressing RGC axon arbor. Images were collected at 20-minute intervals for 8 hours. In each of this movie and Supplementary movie S5-6, a new branch formed during the imaging period and lasted beyond 4 hours is pointed out by arrowhead in the last time point of imaging. (MOV 700 kb)
This movie shows the growth of a Kir2.1 and VAMP-GFP expressing RGC axon arbor. Images were collected at 20-minute intervals for 8 hours. The axon is less exploratory compared with control (Supplementary movie S5), but new branch stability is not significantly affected. A new branch that lasted for more than 4 hours, and was likely stabilized, is pointed out by arrowhead in the last time point of this movie. (MOV 1534 kb)
This movie shows the growth of a VAMPm expressing RGC axon arbor. Images were collected at 20-minute intervals for 8 hours. The axon is less exploratory compared to control (Supplementary movie S5), but new branch stability is not significantly affected. (MOV 591 kb)
About this article
Cite this article
Hua, J., Smear, M., Baier, H. et al. Regulation of axon growth in vivo by activity-based competition. Nature 434, 1022–1026 (2005). https://doi.org/10.1038/nature03409
Spontaneous Neuronal Plasticity in the Contralateral Motor Cortex and Corticospinal Tract after Focal Cortical Infarction in Hypertensive Rats
Journal of Stroke and Cerebrovascular Diseases (2020)
In vivo imaging of evoked calcium responses indicates the intrinsic axonal regenerative capacity of zebrafish
The FASEB Journal (2019)
Biology & Philosophy (2019)
Bioresource Technology (2019)
PLOS Computational Biology (2018)