Deletion of Crmp4 attenuates CSPG-induced inhibition of axonal growth and induces nociceptive recovery after spinal cord injury

Nagai, Jun; Takaya, Ryosuke; Piao, Wenhui; Goshima, Yoshio; Ohshima, Toshio

doi:10.1016/j.mcn.2016.03.006

Cited by 15 publications

(22 citation statements)

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“…The CRMP1-5 family of proteins form heterotetramers and CRMP2 is the most prevalent family member (Goshima et al, 1995;Strittmatter, 1996, 1997;Deo et al, 2004;Schmidt and Strittmatter, 2007). The CRMP family titrates axonal growth in multiple situations (Goshima et al, 1995;Arimura et al, 2005;Niisato et al, 2012Niisato et al, , 2013Khazaei et al, 2014;Nagai et al, 2015Nagai et al, , 2016Takaya et al, 2017). Previous studies have suggested an involvement of CRMPs in myelin ligand signaling.…”

Section: Discussionmentioning

confidence: 99%

Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma

et al. 2019

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After brain or spinal cord trauma, interaction of Nogo-A with neuronal NgR1 limits regenerative axonal sprouting and functional recovery. Cellular signaling by lipid-anchored NgR1 requires a coreceptor but the relevant partner in vivo is not clear. Here, we examined proteins enriched in NgR1 immunoprecipitates by Nogo-A exposure, identifying CRMP2, a cytosolic protein implicated in axon growth inhibition by Semaphorin/Plexin complexes. The Nogo-A-induced association of NgR1 with CRMP2 requires PlexinA2 as a coreceptor. Non-neuronal cells expressing both NgR1 and PlexinA2, but not either protein alone, contract upon Nogo-A exposure. Inhibition of cortical axon regeneration by Nogo-A depends on a NgR1/PlexinA2 genetic interaction because double-heterozygous NgR1 ϩ/Ϫ , PlexinA2 ϩ/Ϫ neurons, but not single-heterozygote neurons, are rescued from Nogo-A inhibition. NgR1 and PlexinA2 also interact genetically in vivo to restrict corticospinal sprouting in mouse cervical spinal cord after unilateral pyramidotomy. Greater post-injury sprouting in NgR1 ϩ/Ϫ , PlexinA2 ϩ/Ϫ mice supports enhanced neurological recovery of a mixed female and male double-heterozygous cohort. Thus, a NgR1/PlexinA2/CRMP2 ternary complex limits neural repair after adult mammalian CNS trauma. Significance StatementSeveral decades of molecular research have suggested that developmental regulation of axon growth is distinct in most regards from titration of axonal regenerative growth after adult CNS trauma. Among adult CNS pathways, the oligodendrocyte Nogo-A inhibition of growth through NgR1 is thought to have little molecular relationship to axonal guidance mechanisms active embryonically. Here, biochemical analysis of NgR1 function uncovered a physical complex with CRMP cytoplasmic mediators, and this led to appreciation of a role for PlexinA2 in concert with NgR1 after adult trauma. The data extend molecular understanding of neural repair after CNS trauma and link it to developmental processes.

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Section: Discussionmentioning

confidence: 99%

Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma

et al. 2019

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“…Collapsin response mediator proteins (CRMPs) are a family of cytosolic phospho-proteins that regulate cytoskeletal dynamics during development and after injury (Alabed et al, 2007;Khazaei et al, 2014;Nagai et al, 2015Nagai et al, , 2016Tan et al, 2015). The CRMP4 family member has two splice isoforms, referred to as the long isoform of CRMP4 (CRMP4L) and the short isoform of CRMP4 (CRMP4S), and is an important neurodevelopmental molecule promoting axonal extension and dendrite branching (Quinn et al, 2003;Niisato et al, 2012;Khazaei et al, 2014;Tan et al, 2015;Cha et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Collapsin Response Mediator Protein 4 (CRMP4) Facilitates Wallerian Degeneration and Axon Regeneration following Sciatic Nerve Injury

Girouard

Simas

Hua

et al. 2020

eNeuro

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In contrast to neurons in the CNS, damaged neurons from the peripheral nervous system (PNS) regenerate, but this process can be slow and imperfect. Successful regeneration is orchestrated by cytoskeletal reorganization at the tip of the proximal axon segment and cytoskeletal disassembly of the distal segment. Collapsin response mediator protein 4 (CRMP4) is a cytosolic phospho-protein that regulates the actin and microtubule cytoskeleton. During development, CRMP4 promotes growth cone formation and dendrite development. Paradoxically, in the adult CNS, CRMP4 impedes axon regeneration. Here, we investigated the involvement of CRMP4 in peripheral nerve injury in male and female Crmp4 À/À mice following sciatic nerve injury. We find that sensory axon regeneration and Wallerian degeneration are impaired in Crmp4 À/À mice following sciatic nerve injury. In vitro analysis of dissociated dorsal root ganglion (DRG) neurons from Crmp4 À/À mice revealed that CRMP4 functions in the proximal axon segment to promote the regrowth of severed DRG neurons and in the distal axon segment where it facilitates Wallerian degeneration through calpain-dependent formation of harmful CRMP4 fragments. These findings reveal an interesting dual role for CRMP4 in proximal and distal axon segments of injured sensory neurons that coordinately facilitate PNS axon regeneration.

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“…Crmp4-/-Increased proximal bifurcation of CA1 pyramidal neurons [57] Axon growth and motor and sensory recovery after SCI [41,88] Enhanced dendritic growth and hyperactivity in olfactory bulb neurons [58,59] Reduced apoptosis, inflammation, and scar formation [41] Decrease in axon extension and growth cone formation [60] Delayed dopaminergic neuron death in the PD model [43] …”

Section: Crmps In Neuronal Degeneration and Regenerationmentioning

confidence: 99%

“…It has been reported that the long-form CRMPs might overwhelm the function of the short form [28]. Furthermore, CRMP4 also interacts with CSPG, possibly through the NgR/GSK3β pathway [88]. Recent studies have demonstrated motor and sensory axon growth after spinal cord injury (SCI) in Crmp4−/− mice [41,88].…”

Section: Axon Degeneration and Regenerationmentioning

confidence: 99%

“…Furthermore, CRMP4 also interacts with CSPG, possibly through the NgR/GSK3β pathway [88]. Recent studies have demonstrated motor and sensory axon growth after spinal cord injury (SCI) in Crmp4−/− mice [41,88]. Moreover, CRMP4 deletion prevents the neurodegeneration of dopaminergic neurons in the substantia nigra par compacta (SNc), and increases axonal viability in the nigro-striatal pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of PD [43].…”

Section: Axon Degeneration and Regenerationmentioning

confidence: 99%

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CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

2016

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Neurodegeneration in the adult mammalian central nervous system (CNS) is fundamentally accelerated by its intrinsic neuronal mechanisms, including its poor regenerative capacity and potent extrinsic inhibitory factors. Thus, the treatment of neurodegenerative diseases faces many obstacles. The degenerative processes, consisting of axonal/dendritic structural disruption, abnormal axonal transport, release of extracellular factors, and inflammation, are often controlled by the cytoskeleton. From this perspective, regulators of the cytoskeleton could potentially be a therapeutic target for neurodegenerative diseases and CNS injury. Collapsin response mediator proteins (CRMPs) are known to regulate the assembly of cytoskeletal proteins in neurons, as well as control axonal growth and neural circuit formation. Recent studies have provided some novel insights into the roles of CRMPs in several inhibitory signaling pathways of neurodegeneration, in addition to its functions in neurological disorders and CNS repair. Here, we summarize the roles of CRMPs in axon regeneration and its emerging functions in non-neuronal cells, especially in inflammatory responses. We also discuss the direct and indirect targeting of CRMPs as a novel therapeutic strategy for neurological diseases.

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Deletion of Crmp4 attenuates CSPG-induced inhibition of axonal growth and induces nociceptive recovery after spinal cord injury

Cited by 15 publications

References 50 publications

Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma

Plexina2 and CRMP2 Signaling Complex Is Activated by Nogo-A-Liganded Ngr1 to Restrict Corticospinal Axon Sprouting after Trauma

Collapsin Response Mediator Protein 4 (CRMP4) Facilitates Wallerian Degeneration and Axon Regeneration following Sciatic Nerve Injury

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

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