Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration

Harada, Chikako; Guo, Xiaoli; Namekata, Kazuhiko; Kimura, Atsuko; Nakamura, Kazuaki; Tanaka, Kohichi; Parada, Luis F.; Harada, Takayuki

doi:10.1038/ncomms1190

Cited by 93 publications

(120 citation statements)

References 48 publications

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“…22 In addition to stimulating the outgrowth of optic nerve axons, BDNF protects RGCs after retinal and optic nerve injury. [46][47][48] Interestingly, GSK-3b is a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. 49 GSK-3b activity has been associated with many psychiatric and neurodegenerative diseases, and it has become increasingly apparent that GSK-3b might be a common therapeutic target for different classes of psychiatric drugs.…”

Section: -37mentioning

confidence: 99%

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

et al. 2013

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Dedicator of cytokinesis 3 (Dock3), a new member of the guanine nucleotide exchange factors for the small GTPase Rac1, promotes axon regeneration following optic nerve injury. In the present study, we found that Dock3 directly binds to the intracellular C-terminus domain of NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that glutamate/aspartate transporter (GLAST) is a major glutamate transporter in the retina, and RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress, and identifies Dock3 signaling as a potential therapeutic target for both neuroprotection and axonal regeneration.

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Section: -37mentioning

confidence: 99%

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

et al. 2013

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“…C57BL/6J mice were obtained from CLEA Japan (Tokyo, Japan) and TrkB KO mice used in this study have previously been generated and characterized (Luikart et al 2005;Namekata et al 2010;Harada et al 2011).…”

Section: Animalsmentioning

confidence: 99%

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

et al. 2012

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Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways.

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“…Our results suggest that Dock3 stimulates both actin rearrangement and microtubule assembly pathways, which are critical for axonal outgrowth. (Harada et al, 2011) and Dock3 transgenic mice . TrkB deletion in the hippocampus and retinal ganglion cells have been confirmed in TrkB GFAP KO (Luikart et al, 2005) and TrkB c-kit KO mice (Harada et al, 2011), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…(Harada et al, 2011) and Dock3 transgenic mice . TrkB deletion in the hippocampus and retinal ganglion cells have been confirmed in TrkB GFAP KO (Luikart et al, 2005) and TrkB c-kit KO mice (Harada et al, 2011), respectively. C57BL/6J mice were obtained from CLEA Japan.…”

Section: Introductionmentioning

confidence: 99%

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolinhomologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3␤ (GSK-3␤) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3␤ and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3␤ was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.

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Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration

Cited by 93 publications

References 48 publications

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

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