Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses

Jun Nagai, Kazuki Owada, Yoshiteru Kitamura, Yoshio Goshima, Toshio Ohshima

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    Central nervous system (CNS) regeneration is restricted by both the lack of neurotrophic responses and the presence of inhibitory factors. As of yet, a common mediator of these two pathways has not been identified. Microtubule dynamics is responsible for several key processes after CNS injuries: intracellular trafficking of receptors for neurotrophic factors, axonal retraction by inhibitory factors, and secondary tissue damages by inflammation and scarring. Kinases regulating microtubule organization, such as Cdk5 or GSK3β, may play pivotal roles during CNS recovery, but the molecular mechanisms remain to be elucidated. Collapsin response mediator protein 2 (CRMP2) stabilizes cytoskeletal polymerization, while CRMP2 phosphorylation by Cdk5 and GSK3β loses its affinity for cytoskeleton proteins, leading to the inhibition of axonal growth. Here, we characterized CRMP2 phosphorylation as the first crucial factor regulating neurotrophic and inhibitory responses after spinal cord injury (SCI). We found that pharmacological inhibition of GSK3β enhanced brain-derived neurotrophic factor (BDNF)-induced axonal growth response in cultured dorsal root ganglion (DRG) neurons. DRG neurons from CRMP2 knock-in (Crmp2KI/KI) mice, where CRMP2 phosphorylation was eliminated, showed elevated sensitivity to BDNF as well. Additionally, cultured Crmp2KI/KI neurons exhibited suppressed axonal growth inhibition by chondroitin sulfate proteoglycan (CSPG). These data suggest a couple of new molecular insights: the BDNF/GSK3β/CRMP2 and CSPG/GSK3β/CRMP2 pathways. Next, we tested the significance of CRMP2 phosphorylation after CNS injury in vivo. The phosphorylation level of CRMP2 was enhanced in the injured spinal cord. Crmp2KI/KI mice exhibited prominent recovery of locomotive and nociceptive functions after SCI, which correlated with the enhanced axonal growth of the motor and sensory neurons. Neuroprotective effects against SCI, such as microtubule stabilization, reduced inflammation, and suppressed scarring were also observed by inhibiting CRMP2 phosphorylation. Therefore, inhibition of CRMP2 phosphorylation demonstrates the unique potential to repair SCI by both enhancing sensitivity to BDNF and reducing inhibitory responses.

    Original languageEnglish
    Pages (from-to)283-295
    Number of pages13
    JournalExperimental Neurology
    Volume277
    DOIs
    Publication statusPublished - 2016 Mar 1

    Fingerprint

    Central Nervous System
    Phosphorylation
    Brain-Derived Neurotrophic Factor
    Spinal Cord Injuries
    Microtubules
    Chondroitin Sulfate Proteoglycans
    Nervous System Trauma
    Spinal Ganglia
    Growth
    Neurons
    Cicatrix
    collapsin response mediator protein-2
    Inflammation
    Nerve Growth Factor Receptors
    Nerve Growth Factors
    Thromboplastin
    Motor Neurons
    Neuroprotective Agents
    Sensory Receptor Cells
    Cytoskeleton

    Keywords

    • Axonal growth inhibitors
    • Cytoskeleton
    • Inflammation
    • Neurotrophin
    • Regeneration
    • Scar
    • Spinal cord injury

    ASJC Scopus subject areas

    • Neurology
    • Developmental Neuroscience

    Cite this

    Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses. / Nagai, Jun; Owada, Kazuki; Kitamura, Yoshiteru; Goshima, Yoshio; Ohshima, Toshio.

    In: Experimental Neurology, Vol. 277, 01.03.2016, p. 283-295.

    Research output: Contribution to journalArticle

    Nagai, Jun ; Owada, Kazuki ; Kitamura, Yoshiteru ; Goshima, Yoshio ; Ohshima, Toshio. / Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses. In: Experimental Neurology. 2016 ; Vol. 277. pp. 283-295.
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