EphB Receptors Couple Dendritic Filopodia Motility to Synapse Formation

Kayser, Matthew S.; Nolt, Mark J.; Dalva, Matthew B.

doi:10.1016/j.neuron.2008.05.007

Cited by 187 publications

(231 citation statements)

References 41 publications

(109 reference statements)

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“…For instance, EphR-Ephrin signal transduction through PAKs plays a critical role in synaptogenesis and spine morphogenesis; activated EphRs bind to Kalirin, a neuronal exchange factor, which in turn stimulates Rac1-PAK-mediated signal transduction to trigger changes in dendritic spine morphology (10). EphR activation also impinges on the trafficking of AMPARs and thereby critically modulates synaptic plasticity (9,12). In this study we identified a novel activity-dependent EphR-signaling pathway that also regulates AMPAR trafficking but is distinct from the aforementioned Kalirin-Rac1 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…These data demonstrate that the integrity of S863 is a (9)(10)(11). In addition, EphB2 forward signaling stimulates Cdc42 and PAK activation to regulate filipodia motility and dendritic spine maintenance (10,12,13). Therefore, we examined whether EphR signaling in cortical neurons affects phosphorylation of GluA1-S863.…”

Section: Ampar Subunit Glua1 Is Phosphorylated At Serine 863 Throughmentioning

confidence: 99%

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Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

Hussain

Thomas

Luo

et al. 2015

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

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AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR-Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine-nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition.A MPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) are the primary mediators of excitatory synaptic transmission in the brain (1). AMPARs are tetrameric ion channels that display distinct functional properties, based on which combinations of subunits, named GluA1-4, are coassembled to form receptor subtypes. Several studies demonstrate that aberrant AMPAR trafficking results in impaired memory and cognition and is associated with numerous neurological disorders (2). Dynamic control of AMPAR recycling to and from synapses is regulated through posttranslational modifications of receptor subunits and through specific interactions with accessory proteins, which in turn can be regulated by neuronal activity. For instance, patterned increases in neuronal activity can initiate signaling cascades that recruit AMPARs into the synaptic membrane and result in an overall strengthening of the synapse; this form of synaptic plasticity is called long-term potentiation (LTP). Conversely, stimulation protocols initiating postsynaptic membrane removal of AMPARs result in a weakening of the synapse and are known as long-term depression (LTD) (3). Several decades of research demonstrate that both LTP and LTD, widely considered the molecular correlates of learning and memory, can be explicitly modulated by the phosphorylation/ dephosphorylation state of AMPAR subunits (3).Members of the Rho GTPase family of proteins are molecular switches, transitioning between inactive/active states to control numerous physiological functions (4, 5). Canonical members include Rho, Rac1, and Cdc42, which regulate many cellular mechanisms, but particularly those involving actin cytoskeletal reorganization, suc...

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Section: Discussionmentioning

confidence: 99%

Section: Ampar Subunit Glua1 Is Phosphorylated At Serine 863 Throughmentioning

confidence: 99%

Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

Hussain

Thomas

Luo

et al. 2015

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

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“…Primary dissociated rat cortical neurons and transfections were conducted as described previously (10,15). Primary dissociated cortical neurons from eB3 −/− mice and wt littermate controls were prepared from postnatal day 1 (P1) mice.…”

Section: Methodsmentioning

confidence: 99%

“…Cells and tissue were fixed and stained as described previously (10,15). Antibodies used were: chicken anti-GFP (1:2,500; Upstate), rabbit anti-Erk1/2 (1:500; Promega), rabbit anti-eB3 (1:50; specificity confirmed by observing loss of staining after incubation with acetone-precipitated proteins from wt but not eB3 −/− brain tissue; Zymed), mouse anti-PSD-95 (1:250; Affinity BioReagents), rabbit anti-SynGAP (1:1,000; Affinity BioReagents), and guinea pig anti-VGlut1 (1:5,000; Chemicon).…”

Section: Methodsmentioning

confidence: 99%

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Trans-synaptic EphB2–ephrin–B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling

McClelland

Hruska

Coenen

et al. 2010

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

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107

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Nervous system function requires tight control over the number of synapses individual neurons receive, but the underlying cellular and molecular mechanisms that regulate synapse number remain obscure. Here we present evidence that a trans-synaptic interaction between EphB2 in the presynaptic compartment and ephrin-B3 in the postsynaptic compartment regulates synapse density and the formation of dendritic spines. Observations in cultured cortical neurons demonstrate that synapse density scales with ephrin-B3 expression level and is controlled by ephrin-B3-dependent competitive cell-cell interactions. RNA interference and biochemical experiments support the model that ephrin-B3 regulates synapse density by directly binding to Erk1/2 to inhibit postsynaptic Ras/mitogen-activated protein kinase signaling. Together these findings define a mechanism that contributes to synapse maturation and controls the number of excitatory synaptic inputs received by individual neurons.N euronal activity is a key determinant of maintaining and controlling the number of synaptic connections (1, 2), but the molecular mechanisms likely to establish the normal density of synaptic contacts are still not well defined (3). Synapse density could be controlled by either secreted or cell surface molecules, but trans-cellular interactions are attractive because of their ability to coordinate events between cells. One family of synaptic adhesion molecules that is well suited to control synapse density is ephrin-Bs (eBs), a family of three (eB1-3) ligands for the EphB family of receptor tyrosine kinases (4). Recent work suggests that ephrins may negatively regulate Ras/MAPK activation in nonvertebrate systems during morphogenesis (5), and that MAPK signaling can negatively regulate presynaptic terminal maturation (6, 7). Here we show that eB3 controls synapse density and the formation of dendritic spines through a competitive postsynaptic mechanism relying on inhibition of MAPK signaling. ResultsEphrin-B3 Expression Level Controls Synapse Density. Early in development [5-10 days in vitro (DIV 5-10)], there are few dendritic spines and synapses that are rapidly added on the dendritic shaft. During this time, eB3 is enriched at excitatory synapses but is also localized to many extrasynaptic locations (Fig. 1A). As neurons mature (DIV 14-21), dendritic spines are formed and become the principal site of excitatory synapses (8); eB3 becomes largely restricted to spine and shaft excitatory synaptic contacts (Fig. 1A and Fig. S1A). The synaptic pattern of eB3 expression suggests that it may be involved in the formation and maturation of excitatory synapses. We asked whether the expression level of eB3 is related to the density of excitatory synapses on individual neurons by plotting the density of endogenous PSD-95 puncta vs. two different measures of eB3 expression: the density of eB3 puncta and the overall intensity of eB3 immunofluorescence. We found that both measures of eB3 expression vary from neuron to neuron and are correlated with PSD-95 punct...

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Actin Reorganization in Nerve Morphogenesis

Singh

Rodrigues

VijayRaghavan

2010

Encyclopedia of Life Sciences

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Anatomists over centuries have described nerve cells which are notable for their diversity of architectures ranging from rather simple cells to highly complex and beautiful shapes. The soma of most neurons have two types of projections – dendrites which receive inputs from the environment or other nerve cells, which specialize in information transfer. The correct shape of a neuron and its connectivity which forms the basis of a functional circuit is crucial for the normal physiology of an animal. Defects in neuronal morphogenesis have been shown to be the cause of several neurological diseases. In this article we focus on a key molecule – actin , a component of the cytoskeleton – that forms the basis of cell shape and growth. We discuss how signals from within the cells and from its developmental milieu influence the organization of actin which in turn impacts on the shape and function of a nerve cell. Key Concepts Actin is enriched in areas of neurons which undergo rapid changes in shape. Actin dynamics is regulated by multiple upstream signals and intracellular effectors. Local destabilization of the actin cytoskeleton is a key downstream event during selection of an axon. Actin dynamics in the growth cone regulates filopodial extension/retraction. Actin cytoskeleton is highly dynamic in dendritic spines. Neuronal activity‐dependent spine enlargement is correlated with a shift in F‐/G‐actin equilibrium towards F‐actin. Rho GTPases are major intracellular regulators of actin dynamics.

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EphB Receptors Couple Dendritic Filopodia Motility to Synapse Formation

Cited by 187 publications

References 41 publications

Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

Trans-synaptic EphB2–ephrin–B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling

Actin Reorganization in Nerve Morphogenesis

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