Chondroitin Sulfate Proteoglycans Down-regulate Spine Formation in Cortical Neurons by Targeting Tropomyosin-related Kinase B (TrkB) Protein

Kurihara, Dai; Yamashita, Toshio

doi:10.1074/jbc.m111.314070

Cited by 44 publications

(35 citation statements)

References 30 publications

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“…MAP2 expression was increased in ChABC-treated and, to a lesser extent, in glypicantreated cultures. Expression of BDNF and FGF2, which have been implicated in some effects of CSPGs (20,21) and HSPGs (22,23) respectively, was examined to determine if these growth factors might be candidate mediators of the ChABC-and glypican-induced increases in MAP2 immunoreactivity. ChABC increased BDNF expression, whereas glypican increased FGF2 expression.…”

Section: Resultsmentioning

confidence: 99%

Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats

Hill

Jin

Mao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Physical and chemical constraints imposed by the periinfarct glial scar may contribute to the limited clinical improvement often observed after ischemic brain injury. To investigate the role of some of these mediators in outcome from cerebral ischemia, we treated rats with the growth-inhibitory chondroitin sulfate proteoglycan neurocan, the growth-stimulating heparan sulfate proteoglycan glypican, or the chondroitin sulfate proteoglycandegrading enzyme chondroitinase ABC. Neurocan, glypican, or chondroitinase ABC was infused directly into the infarct cavity for 7 d, beginning 7 d after middle cerebral artery occlusion. Glypican and chondroitinase ABC reduced glial fibrillary acidic protein immunoreactivity and increased microtubule-associated protein-2 immunoreactivity in the periinfarct region, and glypican-and chondroitinase ABC-treated rats showed behavioral improvement compared with neurocan-or saline-treated rats. Glypican and chondroitinase ABC also increased neurite extension in cortical neuron cultures. Glypican increased fibroblast growth factor-2 expression and chondroitinase ABC increased brain-derived neurotrophic factor expression in these cultures, whereas no such effects were seen following neurocan treatment. Thus, treatment with glypican or enzymatic disruption of neurocan with chondroitinase ABC improves gross anatomical, histological, and functional outcome in the chronic phase of experimental stroke in rats. Changes in growth factor expression and neuritogenesis may help to mediate these effects.astrocyte | astrogliosis | glia P atients who survive an acute stroke are typically left with fixed anatomical deficits and associated functional impairment in the chronic phase of injury, for which few therapeutic options exist. One reason for limited recovery from stroke may be the development of a glial scar at the border between normal and ischemic tissue (1, 2). The glial scar, which contains reactive astrocytes and associated extracellular matrix (ECM) proteins such as chondroitin sulfate proteoglycans (CSPGs) (3, 4), appears to serve a beneficial function in the acute phase of stroke, by confining the lesion and limiting toxic effects on adjacent tissue (5). However, it also inhibits axonal growth and, perhaps, other repair processes (1, 6, 7), thereby interfering with long-term anatomical and functional recovery. Conversely, some ECM proteins, such as the heparan sulfate proteoglycan (HSPG) glypican (8), can stimulate neurite growth after CNS injury (9). The role of these proteins in inhibition of recovery by the postischemic glial scar and the effect of their modification on functional and anatomical outcome from stroke are unknown.CSPGs, a major constituent of the glial scar (10), exist in several isoforms (11). Despite variations in their core proteins, CSPG isoforms share a conserved glycosaminoglycan side chain, which appears to inhibit axonal migration. CSPGs such as neurocan are powerful inhibitors of axonal growth cones and neurite extension in vitro (11), but this effect can be overco...

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Section: Resultsmentioning

confidence: 99%

Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats

Hill

Jin

Mao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Receptor protein tyrosine phosphatase type O (PTPRO) and protein tyrosine phosphatase σ (PTPσ) both dephosphorylate TrkB, providing a negative modulatory effect on the ability of BDNF to stimulate neurite outgrowth and spine morphogenesis (Faux et al, 2007; Gatto et al, 2013; Kurihara and Yamashita, 2012). Like KalSR KO neurons, neurons lacking Slitrk5, a PTPσ interactor, are unable to respond to BDNF (Song et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

2016

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Exogenous brain-derived neurotrophic factor (BDNF), acting through TrkB, is known to promote neurite formation and branching. This response to BDNF was eliminated by inhibition of TrkB kinase and by specific inhibition of the GEF1 domain of Kalirin, which activates Rac1. Neurons from Kalrn knockout mice were unable to activate Rac1 in response to BDNF. BDNF-triggered neurite outgrowth was abolished when Kalrn expression was reduced using shRNA that targets all of the major Kalrn isoforms, and reduced in neurons from Kalrn knockout mice. The Kalrn isoforms expressed early in development also include a GEF2 domain that activates RhoA. However, BDNF-stimulated neurite outgrowth in Kalrn knockout neurons was rescued by expression of Kalirin-7, which includes only the GEF1 domain but lacks the GEF2 domain. Dendritic morphogenesis, which requires spatially restricted, coordinated changes in the actin cytoskeleton and in the organization of microtubules, involves essential contributions from multiple Rho GEFs. Since Tiam1, another Rho GEF, is also required for BDNF-stimulated neurite outgrowth, an inhibitory fragment of Tiam1 (PHn-CC-EX) was tested and found to interfere with both Kalirin and Tiam1 GEF activity. The prolonged TrkB activation observed in response to BDNF in Kalrn knockout neurons and the altered time course and extent of ERK, CREB and Akt activation observed in the absence of Kalrn would be expected to alter the response of these neurons to other regulatory factors.

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“…Several different reports have supported a role for members of the R2A subfamily in synaptogenesis. Thus, RPTPσ has been implicated in modulation of synaptic plasticity by interactions with both TrkB and TrkC (Kurihara and Yamashita, 2012; Takahashi et al, 2011). Most recently, a specific role for RPTPσ in promoting excitatory and RPTPδ in promoting inhibitory synaptic development by interacting with specific slitraks has been reported (Takahashi et al, 2011; Yim et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Receptor protein tyrosine phosphatase σ binds to neurons in the adult mouse brain

Katagiri

Lourie

et al. 2014

Experimental Neurology

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The role of type IIA receptor protein tyrosine phosphatases (RPTPs), which includes LAR, RPTPσ and RPTPδ, in the nervous system is becoming increasingly recognized. Evidence supports a significant role for these RPTPs during the development of the nervous system as well as after injury, and mutations in RPTPs are associated with human disease. However, a major open question is the nature of the ligands that interact with type IIA RPTPs in the adult brain. Candidates include several different proteins as well as the glycosaminoglycan chains of proteoglycans. In order to investigate this problem, we used a receptor affinity probe assay with RPTPσ-AP fusion proteins on sections of adult mouse brain and to cultured neurons. Our results demonstrate that the major binding sites for RPTPσ in adult mouse brain are on neurons and are not proteoglycan GAG chains, as RPTPσ binding overlaps with the neuronal marker NeuN and was not significantly altered by treatments which eliminate chondroitin sulfate, heparan sulfate, or both. We also demonstrate no overlap of binding of RPTPσ with perineuronal nets, and a unique modulation of RPTPσ binding to brain by divalent cations. Our data therefore point to neuronal proteins, rather than CSPGs, as being the ligands for RPTPσ in the adult, uninjured brain.

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Chondroitin Sulfate Proteoglycans Down-regulate Spine Formation in Cortical Neurons by Targeting Tropomyosin-related Kinase B (TrkB) Protein

Cited by 44 publications

References 30 publications

Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats

Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

Receptor protein tyrosine phosphatase σ binds to neurons in the adult mouse brain

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