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

Abstract

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.

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…Conversely, in Nrg1 Type III isoform-specific heterozygous mice, a greater proportion of small caliber axons remained unsorted, and in Nrg1 Type III null mutants even large-caliber axons remain completely unensheathed (Taveggia et al, 2005). Although continued Nrg1/Erbb signaling is not required once myelination has been completed (Atanasoski et al, 2006; Fricker et al, 2009), myelin repair in the peripheral nerves of adult mice recapitulates some of the developmental steps and depends on Nrg1/Erbb signaling, but is considerably more complex (see below).…”

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…During myelinating SC development, Nrg1-III levels on the surface of an axon are thought to directly correlate with axonal diameter, and this promotes the differentiation of SCs associated with large axons into myelinating SCs and thus the generation of myelin [8,9] (reviewed in [10]). Nrg1-III signaling is also critical for RSC development as loss of Nrg1 specifically in sensory axons results in Remak bundles with many more axons, and dramatically reduced RSC ensheathment of axons [11]. Interestingly, however, Nrg1 does not appear to have the same effect on SC fate during remyelination after injury.…”

The Role of Neuregulin-1 In the Response To Nerve Injury

“…Although NRG1 is most potent when presented in the cell membrane at certain low concentrations, soluble NRG1 isoforms (including types I, II and III) can have promyelinating effects in vitro [53,54].To summarize the in vivo evidence, the determination of myelin thickness by NRG1 is dependent on the amount of NRG1 type III expressed on the axonal surface [53]. NRG1 expression on small-diameter axons is also required for the normal ensheathment of these axons by non-myelinating SCs (Figure 2) [55,56]. Deficiency of NRG1 on the axolemma of small-diameter DRG cells results in enlarged Remak bundles with very little SC cytoplasm separating the axons and impaired sensory function [56].…”

“…NRG1 expression on small-diameter axons is also required for the normal ensheathment of these axons by non-myelinating SCs (Figure 2) [55,56]. Deficiency of NRG1 on the axolemma of small-diameter DRG cells results in enlarged Remak bundles with very little SC cytoplasm separating the axons and impaired sensory function [56].…”

“…Scale bars: 500 nm. Reproduced with permission from [56]. Peritoneal macrophages were cultured, these cells are identified by IBA1 immunostaining and nuclear staining with DAPI (A).…”