Abstract
We recently discovered a novel role for neuregulin‐1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)‐like Schwann cells after SCI. Here, we investigate whether Nrg1/ErbB signaling controls the unusual transformation of centrally derived progenitor cells into these functional myelinating Schwann cells after SCI using a fate‐mapping/lineage tracing approach. Specific ablation of Nrg1‐ErbB receptors in central platelet‐derived growth factor receptor alpha (PDGFRα)‐derived lineage cells (using PDGFRαCreERT2/Tomato‐red reporter mice crossed with ErbB3fl/fl/ErbB4fl/fl mice) led to a dramatic reduction in P0‐positive remyelination in the dorsal columns following spinal contusion injury. Central myelination, assessed by Olig2 and proteolipid protein expression, was unchanged. Loss of ErbB signaling in PDGFRα lineage cells also significantly impacted the degree of spontaneous locomotor recovery after SCI, particularly in tests dependent on proprioception. These data have important implications, namely (a) cells from the PDGFRα‐expressing progenitor lineage (which are presumably oligodendrocyte progenitor cells, OPCs) can differentiate into remyelinating PNS‐like Schwann cells after traumatic SCI, (b) this process is controlled by ErbB tyrosine kinase signaling, and (c) this endogenous repair mechanism has significant consequences for functional recovery after SCI. Thus, ErbB tyrosine kinase receptor signaling directly controls the transformation of OPCs from the PDGFRα‐expressing lineage into PNS‐like functional remyelinating Schwann cells after SCI.
Highlights
The lack of adequate therapies for spinal cord injury (SCI) is a major unmet need in medical research (Dietz & Fouad, 2014; Ramer, Ramer, & Bradbury, 2014)
We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)-like Schwann cells after SCI
Using conditional Nrg1 mutant mice, we demonstrated that injury-induced Schwann cell remyelination of central axons in the dorsal columns is dependent on the presence of Nrg1 and contributes significantly to spontaneous locomotor recovery and improved axonal conduction after SCI (Bartus et al, 2016)
Summary
The lack of adequate therapies for spinal cord injury (SCI) is a major unmet need in medical research (Dietz & Fouad, 2014; Ramer, Ramer, & Bradbury, 2014). Removal of adjacent dorsal roots (the source of potential infiltrating Schwann cells) did not affect the extent of Schwann cell myelin in the dorsal columns after SCI, and second, we observed newly dividing cells in close apposition to Schwann cell myelin rings in the SCI epicenter (Bartus et al, 2016) These findings are consistent with the observations made in a model of central focal demyelinating lesions (Zawadzka et al, 2010) and spinal cord contusion injury (Assinck, Duncan, Plemel, et al, 2017), and are in parallel with the concept of endogenous neural stem cell-like responses after central nervous system (CNS) injury that counteract injury-induced tissue loss (Gregoire, Goldenstein, Floriddia, BarnabeHeider, & Fernandes, 2015). Crossing these mutant lines generated mice in which ErbB receptor signaling is exclusively prevented in cells from the CNS resident PDGFRα-expressing progenitor cell lineage With this genetic fate-mapping approach, we reveal that activation of ErbB tyrosine kinase receptors on PDGFRα-expressing central progenitor cells directly controls their transformation into PNS-like myelinating Schwann cells after contusive SCI. We provide direct evidence that remyelinating Schwann cells that are produced de novo in the injured spinal cord comprise a major proportion of the overall remyelinating Schwann cell population, and importantly these remyelinating Schwann cells significantly influence several aspects of spontaneous locomotor recovery, those that depend on adequate proprioceptive input
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