Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function

Cioni, Jean-Michel; Wong, Hovy Ho-Wai; Bressan, Dario; Kodama, Lay; Harris, William A.; Holt, Christine E.

doi:10.1016/j.neuron.2018.01.027

Cited by 49 publications

(64 citation statements)

References 74 publications

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“…In fact, the role of CYFIP2 is very similar to the Arp2/3 inhibitory protein ARPIN that directly inhibits the Arp2/3 complex at the leading edge [23]. In neuronal growth cones, CYFIP2 was found to localize at the tip of filopodia, structures composed of linear actin and not of branched actin [36,41] in line with an inhibitory function of CYFIP2 on branched actin formation we suggest here. In our stable MDA-MB-231 cell line overexpressing GFP-CYFIP2, the enrichment of CYFIP2 at membrane protrusions is less obvious than the enrichment of other subunits of the complex, consistently with the fact that CYFIP2 impairs membrane protrusions [5,42,43].…”

Section: Discussionsupporting

confidence: 79%

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Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

Polesskaya

Boutillon

Wang

et al. 2020

Preprint

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ABSTRACTBranched actin networks polymerized by the Arp2/3 complex are critical for cell migration. The WAVE complex is the major Arp2/3 activator at the leading edge of migrating cells. However, multiple distinct WAVE complexes can be assembled in a cell, due to the combinatorial complexity of paralogous subunits. When systematically analyzing the contribution of each WAVE complex subunit to the metastasis-free survival of breast cancer patients, we found that overexpression of the CYFIP2 subunit was surprisingly associated with good prognosis. Gain and loss of function experiments in transformed and untransformed mammary epithelial cells revealed that cell migration was always inversely related to CYFIP2 levels. The role of CYFIP2 was systematically opposite to the role of the paralogous subunit CYFIP1 or of the NCKAP1 subunit. The specific CYFIP2 function in inhibiting cell migration was related to its unique ability to down-regulate classical pro-migratory WAVE complexes. The anti-migratory function of CYFIP2 was also revealed in migration of prechordal plate cells during gastrulation of the zebrafish embryo, indicating that the unique function of CYFIP2 is critically important in both physiological and pathophysiological migrations.

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Section: Discussionsupporting

confidence: 79%

“…In zebrafish, CYFIP2 loss-of-function mutations result in defective axonal pathfinding in retinal ganglion cells [35]. This function of CYFIP2 is also not redundant with the one of the paralogous subunit, CYFIP1, which is involved in axonal growth [36].…”

Section: Discussionmentioning

confidence: 99%

Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

Polesskaya

Boutillon

Wang

et al. 2020

Preprint

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“…Within a given neuron, FMRP localizes to the soma, developing and mature axons, dendrites, and the base of dendritic spines (Antar et al, 2004(Antar et al, , 2006Ferrari et al, 2007;Zimmer et al, 2017). Because neurons are so highly polarized, transport of mRNAs along the axon and dendrites to undergo local, on-site protein synthesis is key for maintaining proper structural and functional polarity (Bramham, 2008;Cioni et al, 2018;Rangaraju et al, 2017;Tom Dieck et al, 2014). In these subcompartments, FMRP and its homologs, the fragile X-related proteins FXR1P and FXR2P, assemble with other RNA-binding proteins and coding and noncoding RNAs to form large ribonucleoprotein particles or granules that tightly regulate mRNA transport, translation, stability, and degradation (Akins et al, 2012;Korsak et al, 2016;Bagni, 2014a, 2014b).…”

Section: Fmrp At Synapsesmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

248

258

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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“…Despite these molecular functions, in vivo neurobiological mechanisms underlying CYFIP ‐associated brain disorders remain largely unknown and have thus far been investigated mainly for CYFIP1 13–15 . Moreover, CYFIP1 and CYFIP2 have distinct expressions and functions in vivo, 16–19 strongly encouraging further investigation of CYFIP2 in brain function and dysfunction. To address this, we combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses in Cyfip2 heterozygous ( Cyfip2 +/− ) mice to identify specific brain regions, neuronal subtypes, and their functions involved in abnormal behavior and seizure susceptibility of the mice.…”

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confidence: 99%

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

Lee

Zhang

Park

et al. 2020

Annals of Neurology

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Objective Genetic variants of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2) encoding an actin‐regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2‐associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/−) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/− mice and specified a neuronal function mediating its efficacy. Methods We performed behavioral analyses of Cyfip2+/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Results Adult Cyfip2+/− mice exhibited lithium‐responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/− PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/− mice showed increased seizure susceptibility and auditory steady‐state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/− L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/− PFC. Virus‐mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium‐responsive abnormal behavior. Interpretation These results suggest that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/− mice, which can be implicated in CYFIP2‐associated brain disorders. ANN NEUROL 2020;88:526–543

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Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function

Cited by 49 publications

References 74 publications

Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

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