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The Journal of Neuroscience, March 30, 2005, 25(13):3478-3487; doi:10.1523/JNEUROSCI.3766-04.2005

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Cellular/Molecular
Microanatomy of Axon/Glial Signaling during Wallerian Degeneration

Amy D. Guertin,^2 * Dan P. Zhang,^2 * Kimberley S. Mak,² John A. Alberta,² and Haesun A. Kim¹

¹Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, and ²Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

How do myelinated axons signal to the nuclei of cells that enwrap them? The cell bodies of oligodendrocytes and Schwann cells are segregated from axons by multiple layers of bimolecular lipid leaflet and myelin proteins. Conventional signal transduction strategies would seem inadequate to the challenge without special adaptations. Wallerian degeneration provides a model to study axon-to-Schwann cell signaling in the context of nerve injury. We show a hitherto undetected rapid, but transient, activation of the receptor tyrosine kinase erbB2 in myelinating Schwann cells after sciatic nerve axotomy. Deconvolving microscopy using phosphorylation state-specific antibodies shows that erbB2 activation emanates from within the microvilli of Schwann cells, in direct contact with the axons they enwrap. To define the functional role of this transient activation, we used a small molecule antagonist of erbB2 activation (PKI166). The response of myelinating Schwann cells to axotomy is inhibited by PKI166 in vivo. Using neuron/Schwann cell cocultures prepared in compartmentalized cell culture chambers, we show that even transient activation of erbB2 is sufficient to initiate Schwann cell demyelination and that the initiating functions of erbB2 are localized to Schwann cells.

Key words: Wallerian degeneration; Schwann cell; neuregulin; erbB2; PKI166; demyelination

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Received Sep 10, 2004; revised February 16, 2005; accepted February 18, 2005.

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