WAVE/SCAR, a multifunctional complex coordinating different aspects of neuronal connectivity
Open accessAbstract
Although it is well established that the WAVE/SCAR complex transduces Rac1 signaling to trigger Arp2/3-dependent actin nucleation, regulatory mechanisms of this complex and its versatile function in the nervous system are poorly understood. Here we show that the Drosophila proteins SCAR, CYFIP and Kette, orthologs of WAVE/SCAR complex components, all show strong accumulation in axons of the central nervous system and indeed form a complex in vivo. Neuronal defects of SCAR, CYFIP and Kette mutants are, despite the initially proposed function of CYFIP and Kette as SCAR silencers, indistinguishable and are as diverse as ectopic midline crossing and nerve branching as well as synapse undergrowth at the larval neuromuscular junction. The common phenotypes of the single mutants are readily explained by the finding that loss of any one of the three proteins leads to degradation of its partners. As a consequence, each mutant is unambiguously to be judged as defective in multiple components of the complex even though each component affects different signaling pathways. Indeed, SCAR-Arp2/3 signaling is known to control axonogenesis whereas CYFIP signaling to the Fragile X Mental Retardation Protein fly ortholog contributes to synapse morphology. Thus, our results identify the Drosophila WAVE/SCAR complex as a multifunctional unit orchestrating different pathways and aspects of neuronal connectivity.
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Reduction of Cyfip1 or fly Hspc300 affects the level of the other components of the WRC.
“Indeed, it is reported that reduction of Cyfip1 or fly Hspc300 affects the level of the other components of the WRC (Kunda et al., 2003; Schenck et al., 2004; Abekhoukh and Bardoni, 2014; Gautier et al., 2011; Qurashi et al., 2007; De Rubeis et al., 2013).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Schenck et al., 2004
The section “The WAVE/SCAR complex regulates axon pathfinding and motor nerve branching” reports that loss of fly CYFIP reduces the protein levels of its complex partners; Fig. 3 likewise shows loss of the remaining components in CYFIP mutants. The paper does not report that reducing fly HSPC300 has this effect, and its experiment concerns fly CYFIP rather than specifically CYFIP1. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCYFIP is stable only if part of the WRC complex.
“Since we have shown that CYFIP is stable only if part of the WRC complex (Schenck et al., 2004)”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Schenck et al., 2004
In “The WAVE/SCAR complex regulates axon pathfinding and motor nerve branching,” CYFIP protein was undetectable in fly embryonic mutants lacking SCAR or Kette, despite unchanged mRNA levels. This supports dependence on complex partners for stability in the studied embryos, but does not establish the unqualified claim that CYFIP is stable only when incorporated into the complex. (LLM, conf=0.83)
Experimental — accuracy not yet measured
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Cites
Actin Cytoskeleton Regulation in Neuronal Morphogenesis and Structural Plasticity
Luo, L. (2002) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.18.031802.150501 · Cited by 658 · see citing works
Kunda, P., Craig, G., Dominguez, V., & Baum, B. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.005 · Cited by 341 · see citing works
Flagged first, then by citations
Research works printed but not linked: 6
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Cited by
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Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome
Hoeffer, C. A., Sanchez, E., Hagerman, R. J., Mu, Y., Nguyen, D. V., Wong, H., Whelan, A. M., Zukin, R. S., Klann, E., & Tassone, F. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00768.x · Cited by 198 · see citing works
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CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome
Abekhoukh, S., & Bardoni, B. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00081 · Cited by 110 · see citing works
Self-citationAbekhoukh, S., Sahin, H. B., Grossi, M., Zongaro, S., Maurin, T., Madrigal, I., Kazue-Sugioka, D., Raas-Rothschild, A., Doulazmi, M., Carrera, P., et al. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.025809 · Cited by 59 · see citing works
“If post-translational regulation determines the stoichiometry of the WRC members, as previously suggested by several authors (Kunda et al., 2003; Schenck et al., 2004), no phenotype should be observed after Cyfip1 overexpression.”
InfluentialSelf-citation
- Authors
- Schenck, A., Qurashi, A., Carrera, P., Bardoni, B., Diebold, C., Schejter, E., Mandel, J.-L., & Giangrande, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Weizmann Institute of Science (IL)
- Corresponding author
- Giangrande, Angela
- ORCID
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 274
- Issue
- 2
- Pages
- 260-270
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W1989462861
- Cited by
- 76
- References
- 2
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 5 · 2013: 6 · 2012: 3
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3211 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- FRAXA Research Foundation
- Eli Lilly and Company
- Centre National de la Recherche Scientifique
- National Institutes of Health (1r01hd040612-01)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD40612-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- scar tissue, Rac1 signaling, Arp2/3 complex, actin nucleation, axonogenesis, axon midline crossing, nerve branching, FMRP, neuronal connectivity, Drosophila
- MeSH terms
- Animals, Cell Movement, Drosophila melanogaster, Genotype, Humans, Microfilament Proteins, Mutation, Neuromuscular Junction, Neurons, Phenotype, Signal Transduction, RNA-Binding Proteins, In Situ Hybridization, Drosophila Proteins, Macromolecular Substances, Adaptor Proteins, Signal Transducing, Wiskott-Aldrich Syndrome Protein Family, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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