Organization of the Arp2/3 Complex in Hippocampal Spines

Rácz, Bence; Weinberg, Richard J.

doi:10.1523/jneurosci.0756-08.2008

Cited by 75 publications

(74 citation statements)

References 67 publications

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“…Since dendritic spines consist of branched actin filaments, this raised an intriguing question as to the role of the Arp2/3 complex in regulating spine dynamics. Several subunits of the Arp2/3 complex, including Arp2 and Arp3, are concen-trated in dendritic spines, suggesting a functional role for the Arp2/3 complex in spine function [53][54][55][56]. Consistent with this, knockdown of Arp2/3 complex proteins causes a reduction in the number of spines without significantly decreasing the density of filopodia-like protrusions [56,57] (Table 1).…”

Section: Arp2/3 Complexmentioning

confidence: 68%

Actin and Actin-Binding Proteins: Masters of Dendritic Spine Formation, Morphology, and Function

Lin¹,

Webb²

2014

TONEURJ

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Dendritic spines are actin-rich protrusions that comprise the postsynaptic sites of synapses and receive the majority of excitatory synaptic inputs in the central nervous system. These structures are central to cognitive processes, and alterations in their number, size, and morphology are associated with many neurological disorders. Although the actin cytoskeleton is thought to govern spine formation, morphology, and synaptic functions, we are only beginning to understand how modulation of actin reorganization by actin-binding proteins (ABPs) contributes to the function of dendritic spines and synapses. In this review, we discuss what is currently known about the role of ABPs in regulating the formation, morphology, motility, and plasticity of dendritic spines and synapses.

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Section: Arp2/3 Complexmentioning

confidence: 68%

Actin and Actin-Binding Proteins: Masters of Dendritic Spine Formation, Morphology, and Function

Lin¹,

Webb²

2014

TONEURJ

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“…This may be important because cortactin also interacts with shank and connects F-actin to the PSD [68]. Immunoelectron microscopy indicates co-localization of cortactin with Arp2/3 complex in the central core of hippocampal spines and cortactin is known to stabilize Arp2/3 dependent actin filaments [24]. RNAi knockdown of cortactin in hippocampal neurons also leads to reduced spine density [69] (Fig.…”

Section: Regulation Of Rho Gtpase Signaling During Spine Development mentioning

confidence: 92%

“…Interestingly this possibility harkens back to early speculations that changes in the thickness of the spine neck (then termed "stem") could provide a means to information storage by altering the confining properties of the spine head [90]. The spatial arrangement within the spine of different actin pools potentially correlates well with the sub-spine distribution of actin remodeling proteins as assessed by immuno-EM [24,39,91]. These ultrastructural studies show that cofilin, which is required for actin remodeling, is enriched at the tip of the spine.…”

Section: Actin Remodeling In the Spine Is Intimately Paired With Synamentioning

confidence: 99%

“…This complex binds to the side of a preexisting actin filament and nucleates a new actin filament, forming a branch at an approximately 70-degree angle [22,23]. Arp2/3 complex is enriched in dendritic spines, especially around the central core of the spines [24], and the involvement of signaling via Arp2/3 in spine morphology has been documented extensively. Reduction in the number of spines is observed with the knockdown of N-WASP, pharmacological inhibition of N-WASP, or the overexpression of a dominant-negative mutant of N-WASP [25,26].…”

Section: Introductionmentioning

confidence: 99%

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Signaling Through Actin to Regulate Spine Formation and Function

Okada¹,

Soderling²

2014

TONEURJ

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Recent progress has greatly expanded our view of how signaling pathways regulate the actin cytoskeleton in post-synaptic spines. These studies reveal a complex interplay between pathways that highlight the role of the actin cytoskeleton during the development of spines as well as in response to stimuli that modify synaptic strength. This review discusses the results from these studies that include biochemical, cellular, and genetic approaches to understanding excitatory synapse formation and function.

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“…These filopodia-like spines are highly dynamic and protrude and retract frequently; since MIIB is not required for this activity, it is likely that this arises largely from actin polymerization and depolymerization. In contrast, the maturation into a compact, mushroom-shaped structure requires MIIB contractile activity; however, Arp2/3-driven actin polymerization may contribute as well to drive spine head expansion, in analogy with the broad protrusions it mediates in migrating fibroblasts (Rácz and Weinberg, 2008;Hotulainen et al, 2009;Korobova and Svitkina, 2010). Finally, MIIB may also serve to localize signals that affect spine morphology and function, such as…”

Section: Myosin Iib Regulates Post-synaptic Density Organizationmentioning

confidence: 99%

Non-muscle Myosin-IIB and A-actinin-2 Determine Dendritic Spine Morphology and Post-synaptic Organization

Hodges¹

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II AbstractModulation of the actin cytoskeleton dictates the morphological changes associated with dendritic spine dynamics, which serve as the structural basis underlying learning and memory. These micron-sized protrusions mature from a filopodia-like morphology into a mushroom-shape with an enlarged post-synaptic density (PSD). The PSD contains an assembly of synaptic adhesion molecules, glutamate receptors, and signaling scaffolds; many of which respond to glutamate receptor activation and relay signals to the underlying cytoskeleton to induce structural changes in spine and PSD morphology.Non-muscle myosin IIB (MIIB) and α-actinin-2 (ACTN2) directly effect actin organization and both proteins localize to dendritic spines. Both molecules cross-link actin filaments and MIIB also mediates contraction through its ATPase activity.Knockdown of either ACTN2 or MIIB creates an immature spine morphology that fails to mature into a mushroom-shaped spine during development and in response to chemical stimulation. Additionally, loss of ACTN2 increases spine density. Expression of an actin cross-linking, non-contractile mutant, MIIB R709C, showed that spine maturation requires contractile activity. Additionally, di-phosphorylation of the myosin regulatory light chain (RLC) by Rho kinase is required for spine maturation. Inhibition of MIIB activity via blebbistatin treatment, knockdown, or expression of a mono-phosphomimetic mutant of RLC similarly abrogated spine maturation.MIIB and ACTN2 also determine PSD size, morphology, and placement in the spine. Loss of ACTN2 prevents the recruitment and stabilization of a PSD and NMDA-III type glutamate receptors in the spine, resulting in defective synaptic formation.Conversely, a PSD is still seen in neurons with MIIB knocked down, but its loss creates an elongated PSD morphology that is no longer restricted to the spine tip, resulting in a less-clustered distribution of NMDA receptors. In contrast, increased MIIB activity, through either over-expression of wild type MIIB or a RLC di-phosphomimetic mutant, enlarges the PSD area and creates an increased density of mature spines. These observations support a model whereby ACTN2 nucleates PSD formation and recruits the NMDA-type glutamate receptor to the spine, which leads to a functioning synapse.Subsequent NMDA receptor activation increases RLC di-phosphorylation to stimulate MIIB contractility, resulting in a mushroom-shaped spine with an enlarged PSD. IV AcknowledgementsI would like to thank my mentor, Rick Horwitz, for providing a great educational experience throughout my PhD candidacy. He is always available for discussion, albeit regarding my writing, experimental ideas, trouble-shooting, or personal issues. It is through Rick's invaluable coaching that I have learned how to be a successful scientist.

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Organization of the Arp2/3 Complex in Hippocampal Spines

Cited by 75 publications

References 67 publications

Actin and Actin-Binding Proteins: Masters of Dendritic Spine Formation, Morphology, and Function

Actin and Actin-Binding Proteins: Masters of Dendritic Spine Formation, Morphology, and Function

Signaling Through Actin to Regulate Spine Formation and Function

Non-muscle Myosin-IIB and A-actinin-2 Determine Dendritic Spine Morphology and Post-synaptic Organization

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