Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury (original) (raw)
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Journal of Neuroscience, 2011
Neuregulin-1 (NRG1) plays a crucial role in axoglial signaling during the development of the peripheral nervous system, however its importance in adulthood following peripheral nerve injury remains unclear. We utilised Single-neuron Labelling with Inducible Cre-mediated Knockout (SLICK) animals, which enabled visualisation of a subset of adult myelinated sensory and motoneurons neurons in which Nrg1 was inducibly mutated by tamoxifen treatment. In uninjured mice, NRG1 deficient axons and the associated myelin sheath were normal and the neuromuscular junction demonstrated normal apposition of pre-and postsynaptic components. Following sciatic nerve crush, NRG1 ablation resulted in severe defects in remyelination: axons were either hypomyelinated or had no myelin sheath. NRG1 deficient axons were also found to regenerate at a slower rate. Following nerve injury the neuromuscular junction was reinnervated, however excess terminal sprouting was observed. Juxtacrine Neuregulin-1 signaling is therefore dispensable for maintenance of the myelin sheath in adult animals but has a key role in reparative processes following nerve injury.
Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination
Brain, 2013
Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.
Forced Remyelination Promotes Axon Regeneration in a Rat Model of Spinal Cord Injury
International Journal of Molecular Sciences
Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. Multifocal demyelination was induced by injection of ethidium bromide (EB), either at the time of transection or twice during transection and at 5 days post-injury. We demonstrated that the number of oligodendrocyte progenitor cells (OPCs) significantly increased 14 days after demyelination. Most OPCs differentiated into mature oligodendrocytes by 60–90 dpi in double-EB-injected rats; however, most axons were remyelinated by Schwann cells. A significant number of axons passed the injury epicenter and entered the distant segments of the spinal cord in the double-EB-injected rats. Moreover, some serotoninergic fibers, not detected in control animals, grew caudally through the injury site. Behavioral tests ...
Overcoming the molecular inhibitors that impede axonal regeneration following spinal cord injury
The International Spinal Research Trust Annual Research Review 2008, 2008
40 INTRODUCTION Functional recovery from neurological trauma and pathologies, such as spinal cord injury, multiple sclerosis, stroke, and traumatic brain injury is limited by the failure of CNS axons to grow through an inhibitory environment. Molecular analysis of the inhibitors present in the injured CNS have focused on two classes of proteins: the myelin-associated inhibitors Nogo-A, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein, and ephrin-B3; and members of the chondroitin sulphate proteoglycan (CSPG) present in ...
Following spinal cord injury (SCI), a multitude of intrinsic and extrinsic factors adversely affect the gene programs that govern the expression of regeneration-associated genes (RAGs) and the production of a diversity of extracellular matrix molecules (ECM). Insufficient RAG expression in the injured neuron and the presence of inhibitory ECM at the lesion, leads to structural alterations in the axon that perturb the growth machinery, or form an extraneous barrier to axonal regeneration, respectively. Here, the role of myelin, both intact and debris, in antagonizing axon regeneration has been the focus of numerous investigations. These studies have employed antagonizing antibodies and knockout animals to examine how the growth cone of the re-growing axon responds to the presence of myelin and myelin-associated inhibitors (MAIs) within the lesion environment and caudal spinal cord. However, less attention has been placed on how the myelination of the axon after SCI, whether by endogenous glia or exogenously implanted glia, may alter axon regeneration. Here, we examine the intersection between intracellular signaling pathways in neurons and glia that are involved in axon myelination and axon growth, to provide greater insight into how interrogating this complex network of molecular interactions may lead to new therapeutics targeting SCI.
Microenvironmental regulation of oligodendrocyte replacement and remyelination in spinal cord injury
The Journal of Physiology, 2016
Myelin is a proteolipid sheath enwrapping axons in the nervous system that facilitates signal transduction along the axons. In the central nervous system (CNS), oligodendrocytes are specialized glial cells responsible for myelin formation and maintenance. Following spinal cord injury (SCI), oligodendroglia cell death and myelin damage (demyelination) cause chronic axonal damage and irreparable loss of sensory and motor functions. Accumulating evidence shows that replacement of damaged oligodendrocytes and renewal of myelin (remyelination) are Arsalan Alizadeh is a PhD student in Soheila Karimi's Spinal Cord Injury and Stem Cell Laboratory at the University of Manitoba. Using primary glial cultures and in vivo models of spinal cord injury (SCI), his research projects aim to elucidate the role and potential of neuregulin-1 therapy in regulating astrogliosis, neuroinflammation, myelin regeneration and functional recovery following SCI. Soheila Karimi-Abdolrezaee is a neurobiologist at the University of Manitoba with prime expertise in SCI and neural stem cell therapy. Her laboratory focuses on developing cellular and pharmacological approaches to promote remyelination and functional recovery following SCI and demyelinating conditions. Soheila Karimi received her PhD degree in developmental neurobiology with David Schreyer at the University of Saskatchewan. She then undertook a postdoctoral fellowship in spinal cord injury with Michael Fehlings at the Toronto Western Research Institute before establishing her own programme at the University of Manitoba in 2010. This review was presented at the symposium "Axon regeneration and remyelination in the peripheral and central nervous systems", which took place at Physiology 2015, Cardiff, UK between 6-8 July 2015.
International Review of Neurobiology, 2013
Neuregulin 1 (NRG1) is a multifunctional and versatile protein: its numerous isoforms can signal in a paracrine, autocrine or juxtacrine manner, playing a fundamental role during the development of the peripheral nervous system and during the process of nerve repair, suggesting that the treatment with NRG1 could improve functional outcome following injury. Accordingly, the use of NRG1 in vivo has already yielded encouraging results. The aim of this review is to focus on the role played by the different NRG1 isoforms during peripheral nerve regeneration and remyelination and to identify good candidates to be used for the development of tissue engineered medical devices delivering NRG1, with the final goal to promote better nerve repair.
Soluble Neuregulin1 Down-Regulates Myelination Genes in Schwann Cells
Frontiers in Molecular Neuroscience
Peripheral nerves are characterised by the ability to regenerate after injury. Schwann cell activity is fundamental for all steps of peripheral nerve regeneration: immediately after injury they de-differentiate, remove myelin debris, proliferate and repopulate the injured nerve. Soluble Neuregulin1 (NRG1) is a growth factor that is strongly up-regulated and released by Schwann cells immediately after nerve injury. To identify the genes regulated in Schwann cells by soluble NRG1, we performed deep RNA sequencing to generate a transcriptome database and identify all the genes regulated following 6 h stimulation of primary adult rat Schwann cells with soluble recombinant NRG1. Interestingly, the gene ontology analysis of the transcriptome reveals that NRG1 regulates genes belonging to categories that are regulated in the peripheral nerve immediately after an injury. In particular, NRG1 strongly inhibits the expression of genes involved in myelination and in glial cell differentiation, suggesting that NRG1 might be involved in the de-differentiation (or "trans-differentiation") process of Schwann cells from a myelinating to a repair phenotype. Moreover, NRG1 inhibits genes involved in the apoptotic process, and up-regulates genes positively regulating the ribosomal RNA processing, thus suggesting that NRG1 might promote cell survival and stimulate new protein expression. This in vitro transcriptome analysis demonstrates that in Schwann cells NRG1 drives the expression of several genes which partially overlap with genes regulated in vivo after peripheral nerve injury, underlying the pivotal role of NRG1 in the first steps of the nerve regeneration process.
Brain, 2006
Despite considerable progress in recent years, the underlying mechanisms responsible for the failure of axonal regeneration after spinal cord injury (SCI) remain only partially understood. Experimental data have demonstrated that a major impediment to the outgrowth of severed axons is the scar tissue that finally dominates the lesion site and, in severe injuries, is comprised of connective tissue and fluid-filled cysts, surrounded by a dense astroglial scar. Reactive astrocytes and infiltrating cells, such as fibroblasts, produce a dense extracellular matrix (ECM) that represents a physical and molecular barrier to axon regeneration. In the human situation, correlative data on the molecular composition of the scar tissue that forms following traumatic SCI is scarce. A detailed investigation on the expression of putative growth-inhibitory and growth-promoting molecules was therefore performed in samples of post-mortem human spinal cord, taken from patients who died following severe traumatic SCI. The lesion-induced scar could be subdivided into a Schwann cell dominated domain which contained large neuromas and a surrounding dense ECM, and a well delineated astroglial scar that isolated the Schwann cell/ECM rich territories from the intact spinal parenchyma. The axon growth-modulating molecules collagen IV, laminin and fibronectin were all present in the post-traumatic scar tissue. These molecules were almost exclusively found in the Schwann cell-rich domain which had an apparent growth-promoting effect on PNS axons. In the astrocytic domain, these molecules were restricted to blood vessel walls without a co-localization with the few regenerating CNS neurites located in this region.Taken together, these results favour the notion that it is the astroglial compartment that plays a dominant role in preventing CNS axon regeneration. The failure to demonstrate any collagen IV, laminin or fibronectin upregulation associated with the astroglial scar suggests that other molecules may play a more significant role in preventing axon regeneration following human SCI. by guest on June 5, 2013 http://brain.oxfordjournals.org/ Downloaded from