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The Journal of Neuroscience, June 17, 2009, 29(24):7667-7678; doi:10.1523/JNEUROSCI.6053-08.2009

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Development/Plasticity/Repair
Sensory Axon-Derived Neuregulin-1 Is Required for Axoglial Signaling and Normal Sensory Function But Not for Long-Term Axon Maintenance

Florence R. Fricker,¹ Ning Zhu,¹ Christoforos Tsantoulas,¹ Bjarke Abrahamsen,² Mohammed A. Nassar,² Matthew Thakur,¹ Alistair N. Garratt,³ Carmen Birchmeier,³ Stephen B. McMahon,¹ John N. Wood,² and David L. H. Bennett¹

¹Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom, ²Molecular Nociception Group, University College London, London WC1E6BT, United Kingdom, and ³Max Delbrueck Center for Molecular Medicine, 13092 Berlin, Germany

Correspondence should be addressed to Dr. David L. H. Bennett, Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK. Email: david.bennett{at}kcl.ac.uk

Neuregulin-1 has a key role in mediating signaling between axons and Schwann cells during development. A limitation to studying its role in adulthood is the embryonic lethality of global Nrg1 gene deletion. We used the Cre-loxP system to generate transgenic mice in which neuregulin-1 is conditionally ablated in the majority of small-diameter and a proportion of large-diameter sensory neurons that have axons conducting in the C- and A-fiber range, respectively. Sensory neuron-specific neuregulin-1 ablation resulted in abnormally large Remak bundles with axons clustered in "polyaxonal" pockets. The total number of axons in the sural nerve was unchanged, but a greater proportion was unmyelinated. In addition, we observed large-diameter axons that were in a 1:1 relationship with Schwann cells, surrounded by a basal lamina but not myelinated. There was no evidence of DRG or Schwann cell death; the markers of different DRG cell populations and cutaneous innervation were unchanged. These anatomical changes were reflected in a slowing of conduction velocity at the lower end of the A-fiber conduction velocity range and a new population of more rapidly conducting C-fibers that are likely to represent large-diameter axons that have failed to myelinate. Conditional neuregulin-1 ablation resulted in a reduced sensitivity to noxious mechanical stimuli. These findings emphasize the importance of neuregulin-1 in mediating the signaling between axons and both myelinating and nonmyelinating Schwann cells required for normal sensory function. Sensory neuronal survival and axonal maintenance, however, are not dependent on axon-derived neuregulin-1 signaling in adulthood.

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Received Dec. 19, 2008; revised May 5, 2009; accepted May 11, 2009.

Correspondence should be addressed to Dr. David L. H. Bennett, Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK. Email: david.bennett{at}kcl.ac.uk

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