Inhibition by Drebrin of the Actin‐Bundling Activity of Brain Fascin, a Protein Localized in Filopodia of Growth Cones

Sasaki, Yo; Hayashi, Kohei; Shirao, Tomoaki; Ishikawa, Ryoki; Kohama, Kazuhiro

doi:10.1046/j.1471-4159.1996.66030980.x

Cited by 109 publications

(81 citation statements)

References 44 publications

(48 reference statements)

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“…Positive correlation between drebrin content in each spine and its PSD length supports this idea. Drebrin is thought to be involved in the dynamics of actin cytoskeleton through inhibition of actin-myosin interaction Cheng et al, 2000) and competition for other actin-binding proteins, including tropomyosin, α-actinin (Ishikawa et al, 1994), and fascin (Sasaki et al, 1996). The alteration of actin dynamics via drebrin A may enable enlargement of spines by mechanism yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

Kobayashi

Aoki²,

Kojima

et al. 2007

J of Comparative Neurology

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Synaptic activities alter synaptic strengths at the axospinous junctions, and such changes are often accompanied by changes in the size of the postsynaptic spines. We have been exploring the idea that drebrin A, a neuron-specific actin-binding protein localized on the postsynaptic side of excitatory synapses, may be a molecule that links synaptic activity to the shape and content of spines. Here, we performed electron microscopic immunocytochemistry with the nondiffusible gold label to explore the relationship among levels of drebrin A, the NR2A subunit of N-methyl-D-aspartate receptors, and the size of spines in the perirhinal cortex of adult mouse brains. In contrast to the membranous localization within neonatal spines, most immunogold particles for drebrin A were localized to the cytoplasmic core region of spines in mature spines. This distribution suggests that drebrin within adult spines may reorganize the F-actin network at the spine core, in addition to its known neonatal role in spine formation. Drebrin A-immunopositive (DIP) spines exhibited larger spine head areas and longer postsynaptic densities (PSDs) than drebrin A-immunonegative (DIN) spines (P < 0.001). Furthermore, spine head area and PSD lengths correlated positively with drebrin A levels (r = 0.47 and 0.40). The number of synaptic NR2A immunolabels was also higher in DIP spines than in DIN spines, whereas their densities per unit lengths of PSD were not significantly different. These differences between the DIP and the DIN spines indicate that spine sizes and synaptic protein composition of mature brains are regulated, at least in part, by drebrin A levels.

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Section: Discussionmentioning

confidence: 99%

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

Kobayashi

Aoki²,

Kojima

et al. 2007

J of Comparative Neurology

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“…Second, expression data are strongly suggestive of a role for fascin in neuronal morphogenesis. The localization of fascin to growth cone filopodia (Sasaki et al, 1996;Cohan et al, 2001) suggested to the latter authors that fascin promotes "the linear structure and dynamics of filopodia." The failure of singed-mutant neurites to maintain a straight trajectory and uniform caliber provides compelling experimental support for this hypothesis.…”

Section: Unsuspected Neuronal Phenotypes Revealed In Vitromentioning

confidence: 99%

Phenotypes ofDrosophilaBrain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

Kraft¹,

Escobar²,

Narro³

et al. 2006

J. Neurosci.

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Subtle cellular phenotypes in the CNS may evade detection by routine histopathology. Here, we demonstrate the value of primary culture for revealing genetically determined neuronal phenotypes at high resolution. Gamma neurons of Drosophila melanogaster mushroom bodies (MBs) are remodeled during metamorphosis under the control of the steroid hormone 20-hydroxyecdysone (20E). In vitro, wild-type ␥ neurons retain characteristic morphogenetic features, notably a single axon-like dominant primary process and an arbor of short dendrite-like processes, as determined with microtubule-polarity markers. We found three distinct genetically determined phenotypes of cultured neurons from grossly normal brains, suggesting that subtle in vivo attributes are unmasked and amplified in vitro. First, the neurite outgrowth response to 20E is sexually dimorphic, being much greater in female than in male ␥ neurons. Second, the ␥ neuron-specific "naked runt" phenotype results from transgenic insertion of an MB-specific promoter. Third, the recessive, panneuronal "filagree" phenotype maps to singed, which encodes the actin-bundling protein fascin. Fascin deficiency does not impair the 20E response, but neurites fail to maintain their normal, nearly straight trajectory, instead forming curls and hooks. This is accompanied by abnormally distributed filamentous actin. This is the first demonstration of fascin function in neuronal morphogenesis. Our findings, along with the regulation of human Fascin1 (OMIM 602689) by CREB (cAMP response element-binding protein) binding protein, suggest FSCN1 as a candidate gene for developmental brain disorders. We developed an automated method of computing neurite curvature and classifying neurons based on curvature phenotype. This will facilitate detection of genetic and pharmacological modifiers of neuronal defects resulting from fascin deficiency.

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“…It does so by interfering with the actin binding and bundling activities of fascin, ␣-actinin, and tropomyosin (31,32). A similar mechanism might underlie the p116…”

Section: Ripmentioning

confidence: 99%

p116 Is A Novel Filamentous Actin-binding Protein

Mulder

Poland

Gebbink

et al. 2003

Journal of Biological Chemistry

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p116Rip is a ubiquitously expressed protein that was originally identified as a putative binding partner of RhoA in a yeast two-hybrid screen. Overexpression of p116Rip in neuroblastoma cells inhibits RhoA-mediated cell contraction induced by lysophosphatidic acid (LPA); so far, however, the function of p116Rip is unknown. Here we report that p116Rip localizes to filamentous actin (F-actin)-rich structures, including stress fibers and cortical microfilaments, in both serumdeprived and LPA-stimulated cells, with the N terminus (residues 1-382) dictating cytoskeletal localization. In addition, p116Rip is found in the nucleus. Direct interaction or colocalization with RhoA was not detected. We find that p116Rip binds tightly to F-actin (K d ϳ 0 .5 M) via its N-terminal region, while immunoprecipitation assays show that p116Rip is complexed to both F-actin and myosin-II. Purified p116Rip and the F-actin-binding region can bundle F-actin in vitro, as shown by electron microscopy. When overexpressed in NIH3T3 cells, p116Rip disrupts stress fibers and promotes formation of dendrite-like extensions through its N-terminal actinbinding domain; furthermore, overexpressed p116Rip inhibits growth factor-induced lamellipodia formation. Our results indicate that p116Rip is an F-actin-binding protein with in vitro bundling activity and in vivo capability of disassembling the actomyosin-based cytoskeleton.

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Inhibition by Drebrin of the Actin‐Bundling Activity of Brain Fascin, a Protein Localized in Filopodia of Growth Cones

Cited by 109 publications

References 44 publications

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

Drebrin a content correlates with spine head size in the adult mouse cerebral cortex

Phenotypes ofDrosophilaBrain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

p116 Is A Novel Filamentous Actin-binding Protein

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