Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains.
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.
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
Gunnar
G
Dick
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
Chin Lik
CL
Tan
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
Joao Nuno
JN
Alves
Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands.
Erich M E
EME
Ehlert
California Institute of Technology and Howard Hughes Medical Institute, Division of Chemistry and Chemical Engineering, Pasadena, California 91125.
Gregory M
GM
Miller
California Institute of Technology and Howard Hughes Medical Institute, Division of Chemistry and Chemical Engineering, Pasadena, California 91125.
Linda C
LC
Hsieh-Wilson
Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, 001-0021 Sapporo, Japan.
Kazuyuki
K
Sugahara
Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Arie
A
Oosterhof
Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Toin H
TH
van Kuppevelt
Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands; Centre for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081HV Amsterdam, The Netherlands.
Joost
J
Verhaagen
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
James W
JW
Fawcett
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom. Electronic address: jcfk2@cam.ac.uk.
Jessica C F
JCF
Kwok
D020816:Amino Acid Motifs; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D040121:Semaphorin-3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D009419:Nerve Tissue Proteins; C488218:Sema3a protein, rat; D040121:Semaphorin-3A; D002809:Chondroitin Sulfates
Chondroitin Sulfate; Glycosaminoglycan; Neuronal Plasticity; Perineuronal nets; Proteoglycan; Regeneration; Semaphorin; Semaphorin3A