Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains
Open accessAbstract
Chondroitin sulfate (CS) and the CS-rich extracellular matrix structures called perineuronal nets (PNNs) restrict plasticity and regeneration in the CNS. Plasticity is enhanced by chondroitinase ABC treatment that removes CS from its core protein in the chondroitin sulfate proteoglycans or by preventing the formation of PNNs, suggesting that chondroitin sulfate proteoglycans in the PNNs control plasticity. Recently, we have shown that semaphorin3A (Sema3A), a repulsive axon guidance molecule, localizes to the PNNs and is removed by chondroitinase ABC treatment (Vo, T., Carulli, D., Ehlert, E. M., Kwok, J. C., Dick, G., Mecollari, V., Moloney, E. B., Neufeld, G., de Winter, F., Fawcett, J. W., and Verhaagen, J. (2013) Mol. Cell. Neurosci. 56C, 186–200). Sema3A is therefore a candidate for a PNN effector in controlling plasticity. Here, we characterize the interaction of Sema3A with CS of the PNNs. Recombinant Sema3A interacts with CS type E (CS-E), and this interaction is involved in the binding of Sema3A to rat brain-derived PNN glycosaminoglycans, as demonstrated by the use of CS-E blocking antibody GD3G7. In addition, we investigate the release of endogenous Sema3A from rat brain by biochemical and enzymatic extractions. Our results confirm the interaction of Sema3A with CS-E containing glycosaminoglycans in the dense extracellular matrix of rat brain. We also demonstrate that the combination of Sema3A and PNN GAGs is a potent inhibitor of axon growth, and this inhibition is reduced by the CS-E blocking antibody. In conclusion, Sema3A binding to CS-E in the PNNs may be a mechanism whereby PNNs restrict growth and plasticity and may represent a possible point of intervention to facilitate neuronal plasticity. Background: Semaphorin3A (Sema3A) is an axon guidance molecule present in the CNS extracellular matrix and on the perineuronal nets (PNNs). Results: Sema3A interacts with chondroitin sulfate E (CS-E) for anchoring to the PNNs. Conclusion: The binding of Sema3A to CS in the PNNs presents a novel mechanism of PNNs in restricting plasticity. Significance: This finding suggests a novel candidate for intervention in promoting CNS recovery.
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OTX2 and Sema3A bind to 4,6 disulphated GAGs in PNNs, while Nptx2 binds to both 4,6 sulphated GAGs and HA.
“While OTX2 and Sema3A bind to 4,6 disulphated GAGs in the PNNs [23, 28], Nptx2 binds to both 4,6 sulphated GAGs and HA [29].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [28]
Semaphorin 3A regulates synaptic inputs.
“semaphorin 3A to regulate synaptic inputs (Dick et al., 2013;Vo et al., 2013;de Winter et al., 2016)”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Dick et al., 2013
The chemorepulsive molecule semaphorin 3A binds specifically to PNNs via CS-E (found in adults), and this binding exerts an additional level of inhibition of PNN matrix to the growth of neurons.
“The chemorepulsive molecule semaphorin 3A binds specifically to PNNs via CS--E (found in adults), and this binding exerts an additional level of inhibition of PNN matrix to the growth of neurons (Dick et al., 2013;Vo et al., 2013).”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Dick et al., 2013
PNN components include chondroitin sulfate proteoglycans, hyaluronan, tenascin-R, link proteins, Reelin, and semaphorin 3A.
“Their components include chondroitin sulfate proteoglycans (CSPGs), hyaluronan, tenascin-R, link proteins, Reelin and semaphorin 3A (Carulli et al., 2013b; Deepa et al., 2006; Dick et al., 2013; Matthews et al., 2002; Vo et al., 2013a).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Dick et al., 2013
CSPGs, especially their GAG moieties, may inhibit growth by presenting growth-inhibitory proteins.
“Specifically, CSPGs, and particularly their GAG moieties, may act by i) binding to a specific receptor; ii) blocking the growth-promoting activity of integrins; iii) presenting growth-inhibitory proteins.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Dick et al., 2013
Sema3A binds PNNs via CS-E, which is enriched in PNNs.
“Particularly, Sema3A has been shown to bind PNNs via CS-E (Dick et al., 2013), which is enriched in PNNs (Deepa et al., 2006).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Dick et al., 2013
The combination of Sema3A and PNN-GAGs is a potent inhibitor of axon growth.
“Notably, the combination of Sema3A and PNN-GAGs is a potent inhibitor of axon growth (Dick et al., 2013).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Dick et al., 2013
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- Authors
- Dick, G., Tan, C. L., Alves, J. N., Ehlert, E. M. E., Miller, G. M., Hsieh-Wilson, L. C., Sugahara, K., Oosterhof, A., van Kuppevelt, T. H., Verhaagen, J., Fawcett, J. W., & Kwok, J. C. F.
- Affiliations
- University of Oslo (NO)
- University of Cambridge (GB)
- Netherlands Institute for Neuroscience (NL)
- California Institute of Technology (US)
- Hokkaido University (JP)
- Radboud University Medical Center (NL)
- Corresponding author
- Kwok, Jessica C.F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 288
- Issue
- 38
- Pages
- 27384-27395
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3779733
- OpenAlex
- W2000453869
- Cited by
- 160
- References
- 9
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 10 · 2023: 8 · 2022: 8 · 2021: 15 · 2020: 16 · 2019: 12 · 2018: 14 · 2017: 15 · 2016: 10 · 2015: 17 · 2014: 9 · 2013: 1
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Christopher and Dana Reeve Foundation
- California Institute of Technology
- European Commission
- Ministry of Education, Culture, Sports, Science and Technology (24110501)
- National Institutes of Health
- Japan Society for the Promotion of Science (24110501)
- National Institute of General Medical Sciences (R01GM093627)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- semaphorin 3A, perineuronal nets, glycosaminoglycans, chondroitinase ABC, axon guidance, axon growth inhibition, neuroplasticity, extracellular matrix, central nervous system regeneration, neuroprotection, chondroitin sulfate proteoglycans
- MeSH terms
- Animals, Axons, Brain, Brain Chemistry, Chondroitin Sulfates, Extracellular Matrix, Humans, Nerve Tissue Proteins, Neuronal Plasticity, Protein Binding, Amino Acid Motifs, Semaphorin-3A, Mice, Rats, HEK293 Cells
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