Spatially restricted actin‐regulatory signaling contributes to synapse morphology

Nicholson, Daniel A.; Cahill, Michael E.; Tulisiak, Christopher T.; Geinisman, Yuri; Penzes, Peter

doi:10.1111/j.1471-4159.2012.07743.x

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…However, this averaging attenuates underlying nonrandom distributions, so the true in vivo distribution of specific ABPs is likely to be even more restricted. These distinct ABP-defined microdomains imply a highly compartmentalized regulation of the spinoskeleton [179]. This conclusion is supported by observations from live-cell imaging, which also point to functionally discrete sub-spine actin domains [3, 89, 145, 180].…”

Section: Conclusion and Perspectivementioning

confidence: 70%

Microdomains in Forebrain Spines: an Ultrastructural Perspective

Rácz

Weinberg

2012

Mol Neurobiol

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Glutamatergic axons in the mammalian forebrain terminate predominantly onto dendritic spines. Long-term changes in the efficacy of these excitatory synapses are tightly coupled to changes in spine morphology. The reorganization of the actin cytoskeleton underlying this spine “morphing” involves numerous proteins that provide the machinery needed for adaptive cytoskeletal remodeling. Here we review recent literature addressing the chemical architecture of the spine, focusing mainly on actin-binding proteins (ABPs). Accumulating evidence suggests that ABPs are organized into functionally-distinct microdomains within the spine cytoplasm. This functional compartmentalization provides a structural basis for regulation of the spinoskeleton, offering a novel window into mechanisms underlying synaptic plasticity.

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Section: Conclusion and Perspectivementioning

confidence: 70%

Microdomains in Forebrain Spines: an Ultrastructural Perspective

Rácz

Weinberg

2012

Mol Neurobiol

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“…This notion is consistent with results from a study utilizing serial section electron microscopy and immunogold labeling to visualize Kal7 within dendritic spines (Nicholson et al . ). Kal7 was identified in both synaptic (closely associated with the PSD) and extrasynaptic microdomains, which differentially contribute to PSD size and spine volume.…”

Section: Discussionmentioning

confidence: 97%

Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin‐7

Miller

Yan

et al. 2016

Journal of Neurochemistry

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Kalirin (Kal), a dual Rho GDP/GTP exchange factor (GEF), plays essential roles within and outside the nervous system. Tissue-specific, developmentally regulated alternative splicing generates isoforms with one (Kal7) or two (Kal9, Kal12) GEF domains along with a kinase (Kal12) domain; while Kal9 and Kal12 are crucial for neurite outgrowth, Kal7 plays important roles in spine maintenance and synaptic plasticity. Tissue-specific usage of alternate Kalrn promoters (A, B, C, D) places four different peptides before the Sec14 domain. cSec14, with an amphipathic helix encoded by the C-promoter (Kal-C-helix), is the only variant known to interact with phosphoinositides. We sought to elucidate the biological significance of Kalirin promoter usage and lipid binding. While Ex1B expression was predominant early in development, Ex1C expression increased when synaptogenesis occurred. Kal-C-helix-containing Kal7 (cKal7) was enriched at the PSD, present in the microsomal fraction and absent from cytosol; no significant amount of cKal9 or cKal12 could be identified in mouse brain. Similarly, in primary hippocampal neurons, endogenous cKalirin colocalized with PSD95 in dendritic spines, juxtaposed to Vglut1-positive puncta. When expressed in young neurons, bSec14-EGFP was diffusely distributed, while cSec14-EGFP localized to internal puncta. Transfected bKal7-EGFP and cKal7-EGFP localized to dendritic spines and increased spine density in more mature cultured neurons. Although promoter usage did not alter the Rac-GEF activity of Kal7, the synaptic puncta formed by cKal7-EGFP were smaller than those formed by bKal7-EGFP. Molecular modeling predicted a role for Kal-C-helix residue Arg15 in the interaction of cSec14 with phosphoinositides. Consistent with this prediction, mutation of Arg15 to Gln altered the localization of cSec14-EGFP and cKal7-EGFP. These data suggest that phosphoinositide-dependent interactions unique to cKal7 contribute to protein localization and function.

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“…Precise regulation of these actin and microtubule networks is thus central to guide the proper development, plasticity, and long-term stability of these structures (Matus, 2000; Matus et al, 2000; Luo, 2002; Lin and Webb, 2009; Korobova and Svitkina, 2010; Lin and Koleske, 2010; Svitkina et al, 2010; Dent et al, 2011; Nicholson et al, 2012; Penzes and Cahill, 2012; Penzes and Rafalovich, 2012; Saneyoshi and Hayashi, 2012). …”

Section: Cytoskeletal Regulation Is Key To the Maintenance Of Proper mentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Spatially restricted actin‐regulatory signaling contributes to synapse morphology

Cited by 4 publications

References 27 publications

Microdomains in Forebrain Spines: an Ultrastructural Perspective

Microdomains in Forebrain Spines: an Ultrastructural Perspective

Alternate promoter usage generates two subpopulations of the neuronal RhoGEF Kalirin‐7

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

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