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The Journal of Neuroscience, June 10, 2009, 29(23):7450-7458; doi:10.1523/JNEUROSCI.1121-09.2009

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Cellular/Molecular
Axon Initiation and Growth Cone Turning on Bound Protein Gradients

Junyu Mai,¹ Lee Fok,¹ Hongfeng Gao,² Xiang Zhang,^1,3 and Mu-ming Poo²

¹National Science Foundation Nano-Scale Science and Engineering Center and ²Department of Molecular and Cell Biology, University of California, Berkeley, and ³Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

Correspondence should be addressed to either of the following: Dr. Mu-ming Poo, Department of Molecular and Cell Biology, 221 Life Science Addition, University of California, Berkeley, CA 94720, Email: mpoo{at}berkeley.edu; or Dr. Xiang Zhang, Nano-Scale Science and Engineering Center, 3112 Etcheverry Hall, University of California, Berkeley, CA 94720, Email: xiang{at}berkeley.edu

Extracellular gradients of secreted guidance factors are known to guide axon pathfinding and neuronal migration. These factors are likely to bind to cell surfaces or extracellular matrix, but whether and how they may act in bound gradients remains mostly unclear. In this study, we have developed a new technique for rapid production of stable microscopic gradients of substrate-bound proteins by covalent bonding of the proteins with an epoxy-coated glass substrate while they are diffusing in an agarose gel. Using this method, we found that bound gradients of netrin-1 and brain-derived neurotrophic factor (BDNF) can polarize the initiation and turning of axons in cultured hippocampal neurons. Furthermore, bound BDNF gradient caused attractive and repulsive polarizing response on gradients of low- and high-average density of BDNF, respectively. This novel bidirectional response to BDNF depended on the basal level of cAMP in the neuron. Finally, our data showed that the neuron's attractive response to bound BDNF gradient depended on the absolute difference rather than the relative difference in the BDNF density across the neuron, with a minimal effective difference of 1–2 BDNF molecule/µm² on the substrate surface. Thus, substrate-bound guidance factors are highly effective in polarizing axon initiation and growth, and the diffusive printing technique is useful for studying neuronal responses induced by bound protein gradients.

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Received March 7, 2009; accepted April 7, 2009.

Correspondence should be addressed to either of the following: Dr. Mu-ming Poo, Department of Molecular and Cell Biology, 221 Life Science Addition, University of California, Berkeley, CA 94720, Email: mpoo{at}berkeley.edu; or Dr. Xiang Zhang, Nano-Scale Science and Engineering Center, 3112 Etcheverry Hall, University of California, Berkeley, CA 94720, Email: xiang{at}berkeley.edu

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