Authors: Lauren Pulling
Researchers from King’s College London (KCL) and the University of Oxford (UK) have demonstrated that neuregulin-1 (Nrg1) signaling may be crucial for spontaneous spinal cord repair in mice following injury.
This new research, published last week in Brain, raises possibilities for new clinical treatments for patients affected by traumatic spinal cord injury, of whom there are more than 130,000 new cases each year. While there is currently no cure, this new finding points towards treatments that may enhance the CNS’s limited endogenous repair systems.
Following traumatic spinal cord injury, spinal axons undergo acute demyelination, which is then followed by a period of spontaneous remyelination. However, this natural capacity for repair is insufficient for full functional recovery of damaged nerves, leading to a chronic effect on balance, coordination and movement.
Nrg1 is a growth factor known to play a role in myelination in the PNS via an ErbB tyrosine kinase receptor-mediated signaling pathway. The team of researchers from KCL and the University of Oxford, led by Elizabeth Bradbury (Institute of Psychiatry, Psychology and Neuroscience, KCL), investigated whether Nrg1 (encoded by NRG1) is required for Schwann cell-mediated remyelination of central dorsal column axons in mice.
In contused mice with conditional Nrg1 ablation, an absence of Schwann cells within the spinal cord and severe demyelination of dorsal column axons was observed. Furthermore, these mice demonstrated reduced locomotor recovery compared to injured controls.
Bradbury et al. also examined the roles of specific isoforms of Ngr1. They conditionally ablated only the immunoglobulin-containing Nrg1 isoforms, and observed that these isoforms were not required for Schwann cell-mediated remyelination of central axons following injury.
The immunoglobulin-specific Nrg1 mutants did display some reduced locomotor recovery, but not to the extent of global mutants. Additionally, the team performed electrophysiological tests and observed severely impaired axonal conduction in the global mutants but not in the immunoglobulin-specific mutants.
The team also examined the source of remyelinating Schwann cells following injury. When peripheral input was removed, researchers observed that the majority of remyelinating Schwann cells originate within the injured spinal cord. They suggest that Nrg1 may act as a molecular switch to drive the trans-differentiation of central precursor cells into PNS-like Schwann cells coordinate remyelination.
These findings suggest that Nrg1 signaling may be crucial for the endogenous regeneration of central axons following spinal cord injury. Nrg1 signaling may facilitate spontaneous remyelination of central axons and cause central precursor cells to differentiate into PNS-like Schwann cells.
Bradbury commented: “By enhancing this spontaneous response, we may be able to significantly improve spinal cord function after injury. Our research also has wider implications for other disorders of the CNS which share this demyelinating pathology, such as multiple sclerosis.”
Source: Bartus K, Galino J, James N et al. Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury. Brain. doi:10.1093/brain/aww039 (2016); King’s College London press release