ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury

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.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…Additionally, the deletion of just the NRG-1 Type I and II isotypes-which are dispensable for Schwann cell myelination-is sufficient to inhibit open field locomotion (Bartus et al, 2016). To address these concerns, Bartus et al (2019) test, but has no effect on gross open field locomotion (Basso mouse score), like previously reported with the Nrg1 deletion (Bartus et al, 2016;Bartus et al, 2019). However, glial scarring, axon growth, and inflammation were not examined, all of which are impacted by Nrg1-ErbB signaling.…”

“…The myelin constituency of the spinal cord changes following injury. OPCs have been shown to produce myelinating Schwann cells after chemical demyelination (Zawadzka et al, ) as well as following traumatic injuries (Assinck, Duncan, Plemel, et al, ; Bartus et al, ). A population of protein zero (P0) positive Schwann cells derived from OPCs appear to dominate the dorsal regions of the injured cord after dorsal contusion injuries (Assinck, Duncan, Plemel, et al, ).…”

“…Additionally, the deletion of just the NRG‐1 Type I and II isotypes—which are dispensable for Schwann cell myelination—is sufficient to inhibit open field locomotion (Bartus et al, ). To address these concerns, Bartus et al () knocked out the ErbB3/4 receptors from PDGFRα+ cells following SCI and similarly observed impaired Schwann cell myelination from endogenous OPCs, with no reported effect on oligodendrocyte remyelination. Functionally, the deletion of ErbB3/4 results in deficits on an inclined beam walking test, but has no effect on gross open field locomotion (Basso mouse score), like previously reported with the Nrg1 deletion (Bartus et al, ; Bartus et al, ).…”

“…To address these concerns, Bartus et al () knocked out the ErbB3/4 receptors from PDGFRα+ cells following SCI and similarly observed impaired Schwann cell myelination from endogenous OPCs, with no reported effect on oligodendrocyte remyelination. Functionally, the deletion of ErbB3/4 results in deficits on an inclined beam walking test, but has no effect on gross open field locomotion (Basso mouse score), like previously reported with the Nrg1 deletion (Bartus et al, ; Bartus et al, ). However, glial scarring, axon growth, and inflammation were not examined, all of which are impacted by Nrg1‐ErbB signaling.…”

Investigating Nrg1 Signaling in the Regenerating Axolotl Spinal Cord Using Multiplexed FISH

“…Additionally, Nrg1/Erbb2 plays a role in neuronal signaling, including axonal growth and guidance (Bermingham‐McDonogh et al , ; Lopez‐Bendito et al , ; Hancock et al , ), neural stem cell proliferation (Liu et al , ; Sato et al , ), and neural migration (Rio et al , ). Furthermore, SCI in mammals leads to an acute and sustained decrease in Nrg1, and supplementation of Nrg1 after injury can induce neuroprotection (Alizadeh et al , ; ), increase neural progenitor cell proliferation into oligodendrocytes (Whittaker et al , ; Gauthier et al , ), and promote axonal regeneration (Zhang et al , ) and remyelination of naked axons (Bartus et al , ; ). Moreover, Nrg1 is required for multiple regeneration paradigms, including axolotl limb regeneration (Farkas et al , ), axolotl lung regeneration (Jensen et al , ), and heart regeneration in zebrafish (Gemberling et al , ) and mice (Mahmoud et al , ).…”