EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation
Open accessAbstract
The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.
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Array tomography is a powerful tool for high resolution imaging and quantification of synaptic density in vivo.
“using array tomography (AT), a powerful tool for high resolution imaging and quantification of synaptic density in vivo (Greer et al., 2010; Margolis et al., 2010; Micheva and Smith, 2007; Ross et al., 2010).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Margolis et al., 2010
The Results section (‘Ephexin5 negatively regulates excitatory synapse number’; page unavailable) reports using array tomography to quantify excitatory synapses in mouse hippocampus in vivo. The Experimental Procedures confirm use of the method, but our copy does not characterize its imaging resolution or describe it as a ‘powerful tool.’ (LLM, conf=0.82)
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- Authors
- Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., Soskis, M. J., Sahin, M., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Corresponding author
- Greenberg, Michael E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 143
- Issue
- 3
- Pages
- 442-455
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2967209
- OpenAlex
- W2031746153
- Cited by
- 256
- References
- 42
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 12 · 2023: 20 · 2022: 10 · 2021: 14 · 2020: 16 · 2019: 12 · 2018: 13 · 2017: 16 · 2016: 21 · 2015: 20 · 2014: 17 · 2013: 19 · 2012: 27
- FWCI
- 8.80
- 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, 1020 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
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns045500-29)
- National Institute on Aging (5T32AG00222-15, T32AG000222)
- National Institute of Neurological Disorders and Stroke (R01-NS-045500, R01 5R01NS045500)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- EphB receptors, protein degradation, ubiquitination, UBE3A, Angelman syndrome, autism spectrum disorder, synapse maturation, receptor tyrosine kinase signaling
- MeSH terms
- Animals, Child, Child Development Disorders, Pervasive, Embryo, Mammalian, Humans, Synapses, Angelman Syndrome, Dentate Gyrus, Rats, Long-Evans, rhoA GTP-Binding Protein, Receptors, Eph Family, Ubiquitin-Protein Ligases, Mice, Rats, Gene Knockout Techniques
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