Sensory axon-derived neuregulin-1 is required for axoglial signaling and normal sensory function but not for long-term axon maintenance.
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 Adelta-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.
Fricker
Florence R
FR
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
Zhu
Ning
N
Tsantoulas
Christoforos
C
Abrahamsen
Bjarke
B
Nassar
Mohammed A
MA
Thakur
Matthew
M
Garratt
Alistair N
AN
Birchmeier
Carmen
C
McMahon
Stephen B
SB
Wood
John N
JN
Bennett
David L H
DL
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D037102:Lectins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009412:Nerve Fibers / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D020890:Neuregulin-1; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D011930:Reaction Time / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology; D012677:Sensation / Q000235:genetics / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000166:cytology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000294:innervation; D015222:Sodium Channels / Q000235:genetics; D013497:Sural Nerve / Q000473:pathology / Q000648:ultrastructure
D007211:Indoles; D037102:Lectins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D016900:Neurofilament Proteins; C490581:Nrg1 protein, mouse; C568318:Scn10a protein, mouse; D015222:Sodium Channels; C051774:neurofilament protein H; C007293:DAPI; D015740:Calcitonin Gene-Related Peptide