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The Journal of Neuroscience, July 13, 2005, 25(28):6702-6715; doi:10.1523/JNEUROSCI.0871-05.2005

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Development/Plasticity/Repair
Netrin-1 Induces Axon Branching in Developing Cortical Neurons by Frequency-Dependent Calcium Signaling Pathways

Fangjun Tang¹ and Katherine Kalil^1,2

¹Neuroscience Training Program and ²Department of Anatomy, University of Wisconsin-Madison, Madison, Wisconsin 53706

A single axon can innervate multiple targets by collateral branching. Axon branching is thus essential for establishing CNS connectivity. However, surprisingly little is known about the mechanisms by which branching is regulated. Axons often stop elongating before branches develop and anatomical and molecular data suggest that axon branching occurs independent of axon outgrowth. We found that netrin-1 dramatically increases cortical axon branching. Here, we sought to identify intracellular signaling components involved in netrin-1-induced axon branching. Using live cell imaging of dissociated developing cortical neurons, we show that netrin-1 rapidly increases the frequency of repetitive calcium transients. These transients are often restricted to small regions of the axon. Simultaneous imaging of calcium activity and development of axon branches revealed that Ca²⁺ transients coincide spatially and temporally with protrusion of branches from the axon. Remarkably, fully formed branches with motile growth cones could develop de novo within 20 min. Netrin-1-induced Ca²⁺ transients involve release from intracellular stores and Ca²⁺ signaling is essential for netrin-1-induced axon branching. Using techniques to overexpress or suppress kinase activity, we find that calcium/calmodulin-dependent protein kinase II (CaMKII) and mitogen-activated protein kinase (MAPK) are major downstream targets of the netrin-1 calcium signaling pathway and are required for axon branching. CaMKII, but not MAPK, is also involved in axon outgrowth. The role of CaMKII and MAPKs in axon branching is consistent with the sensitivity of these kinases to changes in the frequency Ca²⁺ transients. Together, these novel findings define calcium signaling mechanisms required for development of new axon branches promoted by a guidance cue.

Key words: cortical development; axon guidance; netrin-1; axon branching; calcium transients; CaMKII

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Received Dec 7, 2004; revised June 10, 2005; accepted June 11, 2005.

This article has been cited by other articles:

				M. J. Galazo, V. Martinez-Cerdeno, C. Porrero, and F. Clasca Embryonic and Postnatal Development of the Layer I-Directed ("Matrix") Thalamocortical System in the Rat Cereb Cortex, February 1, 2008; 18(2): 344 - 363. [Abstract] [Full Text] [PDF]

				B. I. Hutchins and K. Kalil Differential Outgrowth of Axons and their Branches Is Regulated by Localized Calcium Transients J. Neurosci., January 2, 2008; 28(1): 143 - 153. [Abstract] [Full Text] [PDF]

				K. Hui, G.-H. Fei, B. J. Saab, J. Su, J. C. Roder, and Z.-P. Feng Neuronal calcium sensor-1 modulation of optimal calcium level for neurite outgrowth Development, December 15, 2007; 134(24): 4479 - 4489. [Abstract] [Full Text] [PDF]

				S. L. Dun, E. Brailoiu, Y. Wang, G. C. Brailoiu, L.-Y. Liu-Chen, J. Yang, J. K. Chang, and N. J. Dun Insulin-Like Peptide 5: Expression in the Mouse Brain and Mobilization of Calcium Endocrinology, July 1, 2006; 147(7): 3243 - 3248. [Abstract] [Full Text] [PDF]

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