Brain-Derived Neurotrophic Factor Regulation of Retinal Growth Cone Filopodial Dynamics Is Mediated through Actin Depolymerizing Factor/Cofilin

Gehler, Scott; Shaw, Alisa E.; Sarmiere, Patrick D.; Bamburg, James R.; Letourneau, Paul C.

doi:10.1523/jneurosci.2836-04.2004

Cited by 110 publications

(102 citation statements)

References 75 publications

(105 reference statements)

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“…BDNF acts via Rho GTPases to regulate the assembly of the actin cytoskeleton in developing neurons (Ozdinler and Erzurumlu, 2001;Gehler et al, 2004;Miyamoto et al, 2006), and there is previous evidence that aspects of these signaling pathways are retained into adulthood in hippocampus . These observations point to BDNF as a logical candidate for a treatment to offset the problems in spine reorganization hypothesized to arise from the fragile X mutation.…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Lauterborn¹,

Rex²,

Kramár³

et al. 2007

J. Neurosci.

225

212

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Mice lacking expression of the fragile X mental retardation 1 (Fmr1) gene have deficits in types of learning that are dependent on the hippocampus. Here, we report that long-term potentiation (LTP) elicited by threshold levels of theta burst afferent stimulation (TBS) is severely impaired in hippocampal field CA1 of young adult Fmr1 knock-out mice. The deficit was not associated with changes in postsynaptic responses to TBS, NMDA receptor activation, or levels of punctate glutamic acid decarboxylase-65/67 immunoreactivity. TBS-induced actin polymerization within dendritic spines was also normal. The LTP impairment was evident within 5 min of induction and, thus, may not be secondary to defects in activity-initiated protein synthesis. Protein levels for both brain-derived neurotrophic factor (BDNF), a neurotrophin that activates pathways involved in spine cytoskeletal reorganization, and its TrkB receptor were comparable between genotypes. BDNF infusion had no effect on baseline transmission or on postsynaptic responses to theta burst stimulation, but nonetheless fully restored LTP in slices from fragile X mice. These results indicate that the fragile X mutation produces a highly selective impairment to LTP, possibly at a step downstream of actin filament assembly, and suggest a means for overcoming this deficit. The possibility of a pharmacological therapy based on these results is discussed.

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Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Lauterborn¹,

Rex²,

Kramár³

et al. 2007

J. Neurosci.

225

212

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“…Results reported in this study are in agreement with Chan et al (56), who showed epidermal growth factor stimulation up-regulates cofilin severing activity in MTLn3 cells lysates, and the work of Bailly et al (77), who demonstrated a decrease in filament length in ultrastructural studies of epidermal growth factor-treated cells. Gehler et al (78) recently reported that BDNF promoted activation of ADF/cofilin by dephosphorylating ADF/cofilin. The severing activity of ADF/cofilin was necessary to mediate the effects of BDNF because a nonsevering mutant of ADF/cofilin blocked the effects of BDNF on filopodial dynamics.…”

Section: Discussionmentioning

confidence: 99%

Myosin Phosphatase and Cofilin Mediate cAMP/cAMP-dependent Protein Kinase-induced Decline in Endothelial Cell Isometric Tension and Myosin II Regulatory Light Chain Phosphorylation

Goeckeler

Wysolmerski

2005

Journal of Biological Chemistry

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This study determined the effects of increased intracellular cAMP and cAMP-dependent protein kinase activation on endothelial cell basal and thrombin-induced isometric tension development. Elevation of cAMP and maximal cAMP-dependent protein kinase activation induced by 10 M forskolin, 40 M 3-isobutyl-1-methylxanthine caused a 50% reduction in myosin II regulatory light chain (RLC) phosphorylation and a 35% drop in isometric tension, but it did not inhibit thrombin-stimulated increases in RLC phosphorylation and isometric tension. Elevation of cAMP did not alter myosin light chain kinase catalytic activity. However, direct inhibition of myosin light chain kinase with KT5926 resulted in a 90% decrease in RLC phosphorylation and only a minimal decrease in isometric tension, but it prevented thrombin-induced increases in RLC phosphorylation and isometric tension development. We showed that elevated cAMP increases phosphorylation of RhoA 10-fold, and this is accompanied by a 60% decrease in RhoA activity and a 78% increase in RLC phosphatase activity. Evidence is presented that it is this inactivation of RhoA that regulates the decrease in isometric tension through a pathway involving cofilin. Activated cofilin correlates with increased F-actin severing activity in cell extracts from monolayers treated with forskolin/3-isobutyl-1-methylxanthine. Pretreatment of cultures with tautomycin, a protein phosphatase type 1 inhibitor, blocked the effect of cAMP on 1) the dephosphorylation of cofilin, 2) the decrease in RLC phosphorylation, and 3) the decrease in isometric tension. Together, these data provide in vivo evidence that elevated intracellular cAMP regulates endothelial cell isometric tension and RLC phosphorylation through inhibition of RhoA signaling and its downstream pathways that regulate myosin II activity and actin reorganization.Endothelial cells lining blood vessels form a continuous layer that constrains proteins and blood elements to the vascular lumen. Disruption of the continuous endothelial barrier leads to an increase in permeability and development of edema, a hallmark of acute and chronic inflammation. Chemical or inflammatory mediators activate signaling pathways that cause endothelial cells to contract forming gaps between adjacent cells leading to an increase in vascular permeability. Several laboratories studying methods to inhibit endothelial cell contraction and vascular permeability have demonstrated that elevation of intracellular cAMP augments barrier function and prevents increases in permeability to a wide range of inflammatory agonists. The primary pathway implicated in preventing increases in permeability is believed to occur through the activation of adenylate cyclase, accumulation of intracellular cAMP, and activation of PKA.2 Even though there are numerous reports (1-5) implicating cAMP/PKA in enhancing barrier function and inhibiting endothelial cell contraction, the mechanism by which cAMP/PKA protects vascular integrity is poorly understood.cAMP is a primary mediator of the biolo...

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“…JNK has been reported to promote PDGF-BB-induced dephosphorylation of cofilin (37). The dephosphorylated form of cofilin is active and can influence filopodial dynamics (38,39) and neurite outgrowth (40 -42) by regulating F-actin dynamics. To investigate a more direct mechanism for the effect of JIP3 on axon elongation, we performed immunofluorescence analysis of the levels of phosphorylated cofilin (p-cofilin) in hippocampal neurons (Fig.…”

Section: Jip3 Regulates Actin Dynamics At Axon Tips Through the Jnkcomentioning

confidence: 99%

c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner

Sun

Zhai

et al. 2013

Journal of Biological Chemistry

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Brain-Derived Neurotrophic Factor Regulation of Retinal Growth Cone Filopodial Dynamics Is Mediated through Actin Depolymerizing Factor/Cofilin

Cited by 110 publications

References 75 publications

Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Myosin Phosphatase and Cofilin Mediate cAMP/cAMP-dependent Protein Kinase-induced Decline in Endothelial Cell Isometric Tension and Myosin II Regulatory Light Chain Phosphorylation

c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner

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