Bral1: its role in diffusion barrier formation and conduction velocity in the CNS
Open accessAbstract
At the nodes of Ranvier, excitable axon membranes are exposed directly to the extracellular fluid. Cations are accumulated and depleted in the local extracellular nodal region during action potential propagation, but the impact of the extranodal micromilieu on signal propagation still remains unclear. Brain-specific hyaluronan-binding link protein, Bral1, colocalizes and forms complexes with negatively charged extracellular matrix (ECM) proteins, such as versican V2 and brevican, at the nodes of Ranvier in the myelinated white matter. The link protein family, including Bral1, appears to be the linchpin of these hyaluronan-bound ECM complexes. Here we report that the hyaluronan-associated ECM no longer shows a nodal pattern and that CNS nerve conduction is markedly decreased in Bral1-deficient mice even though there were no differences between wild-type and mutant mice in the clustering or transition of ion channels at the nodes or in the tissue morphology around the nodes of Ranvier. However, changes in the extracellular space diffusion parameters, measured by the real-time iontophoretic method and diffusion-weighted magnetic resonance imaging (MRI), suggest a reduction in the diffusion hindrances in the white matter of mutant mice. These findings provide a better understanding of the mechanisms underlying the accumulation of cations due to diffusion barriers around the nodes during saltatory conduction, which further implies the importance of the Bral1-based extramilieu for neuronal conductivity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The perinodal net creates an ion diffusion barrier by acting as a cation buffer at nodes of Ranvier.
“This structure functions to create an ion diffusion barrier by acting as a cation buffer at the nodes of Ranvier (Bekku et al., 2010)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Bekku et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
Church, G. M., & Gilbert, W. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.7.1991 · Cited by 8,213 · see citing works
Diffusion in Brain Extracellular Space
Syková, E., & Nicholson, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00027.2007 · Cited by 1,481 · see citing works
Self-citationExtracellular space structure revealed by diffusion analysis
Nicholson, C., & Syková, E. (1998) · Trends in Neurosciences · doi:10.1016/s0166-2236(98)01261-2 · Cited by 914 · see citing works
Self-citationNicholson, C., & Phillips, J. M. (1981) · The Journal of Physiology · doi:10.1113/jphysiol.1981.sp013981 · Cited by 785 · see citing works
CNS Myelin and Sertoli Cell Tight Junction Strands Are Absent in Osp/Claudin-11 Null Mice
Gow, A., Southwood, C. M., Li, J. S., Pariali, M., Riordan, G. P., Brodie, S. E., Danias, J., Bronstein, J. M., Kachar, B., & Lazzarini, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)81553-6 · Cited by 702 · see citing works
The local differentiation of myelinated axons at nodes of Ranvier
Poliak, S., & Peles, E. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1253 · Cited by 673 · see citing works
Sodium channel Na <sub>v</sub> 1.6 is localized at nodes of Ranvier, dendrites, and synapses
Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E., & Levinson, S. R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090034797 · Cited by 649 · see citing works
Devaux, J. J., Kleopa, K. A., Cooper, E. C., & Scherer, S. S. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4512-03.2004 · Cited by 451 · see citing works
Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon.
Boiko, T., Rasband, M., Levinson, S., Caldwell, J., Mandel, G., Trimmer, J. S., & Matthews, G. (2001) · Neuron · doi:10.1016/s0896-6273(01)00265-3 · Cited by 434 · see citing works
Carulli, D., Rhodes, K. E., Brown, D. J., Bonnert, T. P., Pollack, S. J., Oliver, K., Strata, P., & Fawcett, J. W. (2006) · Journal of Comparative Neurology · doi:10.1002/cne.20822 · Cited by 341 · see citing works
Aspberg, A., Miura, R., Bourdoulous, S., Shimonaka, M., Heinegård, D., Schachner, M., Ruoslahti, E., & Yamaguchi, Y. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.19.10116 · Cited by 275 · see citing works
Neurofascin assembles a specialized extracellular matrix at the axon initial segment
Hedstrom, K. L., Xu, X., Ogawa, Y., Frischknecht, R., Seidenbecher, C. I., Shrager, P., & Rasband, M. N. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200705119 · Cited by 268 · see citing works
Extrasynaptic volume transmission and diffusion parameters of the extracellular space
Syková, E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.06.077 · Cited by 265 · see citing works
Self-citationSrinivasan, J., Schachner, M., & Catterall, W. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15753 · Cited by 249 · see citing works
Weber, P., Bartsch, U., Rasband, M. N., Czaniera, R., Lang, Y., Bluethmann, H., Margolis, R. U., Levinson, S. R., Shrager, P., Montag, D., et al. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-11-04245.1999 · Cited by 247 · see citing works
Tenascin-R Is a Functional Modulator of Sodium Channel β Subunits
Xiao, Z., Ragsdale, D. S., Malhotra, J. D., Mattei, L. N., Braun, P. E., Schachner, M., & Isom, L. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.37.26511 · Cited by 211 · see citing works
Diffusion barriers evoked in the rat cortex by reactive astrogliosis
Roitbak, T., & Sykov�, E. (1999) · Glia · doi:10.1002/(sici)1098-1136(199910)28:1 · Cited by 208 · see citing works
Self-citationNeurocan Is Dispensable for Brain Development
Zhou, X.-H., Brakebusch, C., Matthies, H., Oohashi, T., Hirsch, E., Moser, M., Krug, M., Seidenbecher, C. I., Boeckers, T. M., Rauch, U., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.17.5970-5978.2001 · Cited by 206 · see citing works
Self-citationNicholson, C. (1993) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(93)90092-6 · Cited by 203 · see citing works
Mice lacking link protein develop dwarfism and craniofacial abnormalities
Watanabe, H., & Yamada, Y. (1999) · Nature Genetics · doi:10.1038/6016 · Cited by 190 · see citing works
Zonta, B., Tait, S., Melrose, S., Anderson, H., Harroch, S., Higginson, J., Sherman, D. L., & Brophy, P. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200712154 · Cited by 188 · see citing works
A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β
Ratcliffe, C. F., Qu, Y., McCormick, K. A., Tibbs, V. C., Dixon, J. E., Scheuer, T., & Catterall, W. A. (2000) · Nature Neuroscience · doi:10.1038/74805 · Cited by 182 · see citing works
Syková, E., Svoboda, J., Polák, J., et al. (1994) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1994.37 · Cited by 181 · see citing works
Self-citationCarulli, D., Rhodes, K. E., & Fawcett, J. W. (2007) · Journal of Comparative Neurology · doi:10.1002/cne.21231 · Cited by 158 · see citing works
CSF-1 deficiency in mice results in abnormal brain development
Michaelson, M. D., Bieri, P. L., Mehler, M. F., Xu, H., Arezzo, J. C., Pollard, J. W., & Kessler, J. A. (1996) · Development · doi:10.1242/dev.122.9.2661 · Cited by 129 · see citing works
Oohashi, T., Hirakawa, S., Bekku, Y., Rauch, U., Zimmermann, D. R., Su, W.-D., Ohtsuka, A., Murakami, T., & Ninomiya, Y. (2002) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.1061 · Cited by 124 · see citing works
Self-citationExtracellular matrix glycoproteins and diffusion barriers in human astrocytic tumours
Zámečnı́k, J., Vargová, L., Homola, A., Kodet, R., & Syková, E. (2004) · Neuropathology and Applied Neurobiology · doi:10.1046/j.0305-1846.2003.00541.x · Cited by 123 · see citing works
Self-citationNo Obvious Abnormality in Mice Deficient in Receptor Protein Tyrosine Phosphatase β
Harroch, S., Palmeri, M., Rosenbluth, J. M., Custer, A., Okigaki, M., Shrager, P., Blum, M., Buxbaum, J. D., & Schlessinger, J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.20.7706-7715.2000 · Cited by 115 · see citing works
Bekku, Y., Su, W.-D., Hirakawa, S., Fässler, R., Ohtsuka, A., Kang, J. S., Sanders, J., Murakami, T., Ninomiya, Y., & Oohashi, T. (2003) · Molecular and Cellular Neuroscience · doi:10.1016/s1044-7431(03)00133-7 · Cited by 114 · see citing works
Self-citationEvolution of anisotropic diffusion in the developing rat corpus callosum
Voříšek, I., & Syková, E. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.78.2.912 · Cited by 113 · see citing works
Self-citationRice, M. E., Okada, Y., & Nicholson, C. (1993) · Journal of Neurophysiology · doi:10.1152/jn.1993.70.5.2035 · Cited by 105 · see citing works
Bekku, Y., Rauch, U., Ninomiya, Y., & Oohashi, T. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05873.x · Cited by 104 · see citing works
Self-citationBinding of calcium to glycosaminoglycans: An equilibrium dialysis study
Hunter, G. K., Wong, K., & Kim, J. J. (1988) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(88)90437-7 · Cited by 101 · see citing works
On the existence of a cartilage‐like proteoglycan and link proteins in the central nervous system
Asher, R. A., Scheibe, R. J., Keiser, H. D., & Bignami, A. (1995) · Glia · doi:10.1002/glia.440130406 · Cited by 100 · see citing works
Lopreore, C. L., Bartol, T. M., Coggan, J. S., Keller, D. X., Sosinsky, G. E., Ellisman, M. H., & B, T. J. S. A. (2008) · Biophysical Journal · doi:10.1529/biophysj.108.132167 · Cited by 94 · see citing works
Reduced extracellular space in the brain of tenascin‐R‐ and HNK‐1‐sulphotransferase deficient mice
Syková, E., Voříšek, I., Mazel, T., Antonova, T., & Schachner, M. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04375.x · Cited by 73 · cited 21× · see citing works
“We show that the hyaluronan-associated ECM no longer shows a nodal pattern and CNS nerve conduction is markedly decreased even though there are no changes in the nodal components in Bral1-deficient mice; however, the ECS diffusion parameters suggest facilitated diffusion in the white matter of mutant mice.”
BackgroundMethodInfluentialSelf-citationHirakawa, S., Oohashi, T., Su, W.-D., Yoshioka, H., MURAKAMI, T., Arata, J., & Ninomiya, Y. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3583 · Cited by 70 · see citing works
Self-citationHeterogeneous and anisotropic diffusion in the developing rat spinal cord
Prokopová, Š., Vargová, L., & Syková, E. (1997) · Neuroreport · doi:10.1097/00001756-199711100-00022 · Cited by 62 · see citing works
Self-citationExtrasynaptic transmission and the diffusion parameters of the extracellular space
Syková, E., & Vargová, L. (2007) · Neurochemistry International · doi:10.1016/j.neuint.2007.04.007 · Cited by 62 · see citing works
Self-citationSuwan, K., Choocheep, K., Hatano, S., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806927200 · Cited by 52 · see citing works
Lynn, B. D., Li, X., Cattini, P. A., Turley, E. A., & Nagy, J. I. (2001) · The Journal of Comparative Neurology · doi:10.1002/cne.1353 · Cited by 50 · see citing works
Flash and pattern reversal visual evoked potentials in C57BL/6J and B6CBAF1/J mice
Strain, G. M., & Tedford, B. L. (1993) · Brain Research Bulletin · doi:10.1016/0361-9230(93)90319-7 · Cited by 41 · see citing works
Link protein can retard the degradation of hyaluronan in proteoglycan aggregates
Rodriguez, E., & Roughley, P. J. (2006) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2006.02.008 · Cited by 35 · see citing works
Magnesium Deficiency Differentially Affects the Retina and Visual Cortex of Intact Rats
Goto, Y., Tobimatsu, S., & Furuta, A. (2001) · Journal of Nutrition · doi:10.1093/jn/131.9.2378 · Cited by 18 · see citing works
Self-citationIon binding: patterns of 'affinity' depending on types of acid groups.
Scott, J. E. (1989) · PubMed · Cited by 13 · see citing works
Sykové, E. (1992) · Progress in sensory physiology · doi:10.1007/978-3-642-76937-5_1 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Syková E (1992) Ionic and volume changes in the microenvironment of nerve and receptor cells. In: Progress in sensory physiology (Otterson D, ed), pp 1-167. Berlin: Springer.
Cited by
Sorted by citations
The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function
Fawcett, J. W., Oohashi, T., & Pizzorusso, T. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0196-3 · Cited by 589 · see citing works
Self-citationPathophysiology of the brain extracellular matrix: a new target for remyelination
Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S., & Yong, V. W. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3550 · Cited by 549 · see citing works
Extracellular Matrix: Functions in the Nervous System
Barros, C. S., Franco, S. J., & Muller, U. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005108 · Cited by 506 · see citing works
Extracellular matrix and perineuronal nets in CNS repair
Kwok, J. C. F., Dick, G., Wang, D., & Fawcett, J. W. (2011) · Developmental Neurobiology · doi:10.1002/dneu.20974 · Cited by 395 · see citing works
The perineuronal net and the control of CNS plasticity
Wang, D., & Fawcett, J. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1375-y · Cited by 373 · see citing works
Brain Extracellular Space: The Final Frontier of Neuroscience
Nicholson, C., & Hrabětová, S. (2017) · Biophysical Journal · doi:10.1016/j.bpj.2017.06.052 · Cited by 321 · see citing works
Three mechanisms assemble central nervous system nodes of Ranvier
Susuki, K., Chang, K.-J., Zollinger, D. R., Liu, Y., Ogawa, Y., Eshed-Eisenbach, Y., Dours-Zimmermann, M. T., Oses-Prieto, J. A., Burlingame, A. L., Seidenbecher, C. I., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.03.005 · Cited by 186 · see citing works
Self-citationMorawski, M., Reinert, T., Meyer-Klaucke, W., Wagner, F. E., Tröger, W., Reinert, A., Jäger, C., Brückner, G., & Arendt, T. (2015) · Scientific Reports · doi:10.1038/srep16471 · Cited by 116 · see citing works
Perineuronal nets and schizophrenia: The importance of neuronal coatings
Bitanihirwe, B. K. Y., & Woo, T.-U. W. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.03.018 · Cited by 95 · see citing works
ECM in brain aging and dementia
Morawski, M., Filippov, M., Tzinia, A., Tsilibary, E., & Vargova, L. (2014) · Progress in Brain Research · doi:10.1016/b978-0-444-63486-3.00010-4 · Cited by 84 · see citing works
Bekku, Y., Saito, M., Moser, M., Fuchigami, M., Maehara, A., Nakayama, M., Kusachi, S., Ninomiya, Y., & Oohashi, T. (2012) · Journal of Comparative Neurology · doi:10.1002/cne.23009 · Cited by 65 · see citing works
Self-citationHyaluronan synthesis by developing cortical neurons in vitro
Fowke, T. M., Karunasinghe, R. N., Bai, J.-Z., Jordan, S., Gunn, A. J., & Dean, J. M. (2017) · Scientific Reports · doi:10.1038/srep44135 · Cited by 47 · see citing works
- Authors
- Bekku, Y., Vargová, L., Goto, Y., Vorísek, I., Dmytrenko, L., Narasaki, M., Ohtsuka, A., Fässler, R., Ninomiya, Y., Syková, E., & Oohashi, T.
- Affiliations
- Okayama University (JP)
- Czech Academy of Sciences (CZ)
- Max Planck Society (DE)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Oohashi, Toshitaka
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-02-24
- Volume
- 30
- Issue
- 8
- Pages
- 3113-3123
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6633924
- OpenAlex
- W2058162424
- Cited by
- 123
- References
- 47
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 4 · 2017: 8 · 2016: 6 · 2015: 11 · 2014: 13 · 2013: 11 · 2012: 7
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Ministerstvo Školství, Mládeže a Tělovýchovy (1M0538)
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- Akademie Věd České Republiky (1M0538)
- Ryobi Teien Memory Foundation
- Japan Society for the Promotion of Science (15591857, 20791195, 18791206, 17046012)
- National Institute of Neurological Disorders and Stroke (F32NS009915)
- Advanced Scientific Computing Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- nodes of Ranvier, extracellular matrix, diffusion barrier, saltatory conduction, action potential propagation, cation accumulation, brevican
- MeSH terms
- Proteoglycan Link Protein, Action Potentials, Animals, Cations, Cell Membrane, Central Nervous System, Diffusion, Extracellular Matrix, Female, Hyaluronic Acid, Ion Channels, Male, Mice, Inbred ICR, Nerve Fibers, Myelinated, Nerve Tissue Proteins, Neural Conduction, Proteoglycans, Ranvier's Nodes, Ion Channel Gating, Mice, Knockout, Diffusion Magnetic Resonance Imaging, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
