PUBLICATION

Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Authors
Kolb, J., Tsata, V., John, N., Kim, K., Möckel, C., Rosso, G., Kurbel, V., Parmar, A., Sharma, G., Karandasheva, K., Abuhattum, S., Lyraki, O., Beck, T., Müller, P., Schlüßler, R., Frischknecht, R., Wehner, A., Krombholz, N., Steigenberger, B., Beis, D., Takeoka, A., Blümcke, I., Möllmert, S., Singh, K., Guck, J., Kobow, K., Wehner, D.
ID
ZDB-PUB-231027-61
Date
2023
Source
Nature communications   14: 68146814 (Journal)
Registered Authors
Beis, Dimitris, Kolb, Julia, Wehner, Anja, Wehner, Daniel
Keywords
none
MeSH Terms
  • Animals
  • Axons
  • Central Nervous System
  • Chondroitin Sulfate Proteoglycans
  • Decorin
  • Extracellular Matrix Proteins
  • Humans
  • Mammals
  • Nerve Regeneration
  • Proteoglycans*
  • Small Leucine-Rich Proteoglycans*
  • Zebrafish
(all 12)
PubMed
37884489 Full text @ Nat. Commun.
Abstract
Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.
Genes / Markers
Marker Marker Type Name
anxa2aGENEannexin A2a
anxa2bGENEannexin A2b
anxa4GENEannexin A4
aspnGENEasporin (LRR class 1)
bgnaGENEbiglycan a
bgnbGENEbiglycan b
chadGENEchondroadherin
chadlaGENEchondroadherin-like a
chadlbGENEchondroadherin-like b
col11a1bGENEcollagen, type XI, alpha 1b
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Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    mps3TgTransgenic Insertion
      mps7TgTransgenic Insertion
      mps9TgTransgenic Insertion
        mps10TgTransgenic Insertion
          mps11TgTransgenic Insertion
            mps12TgTransgenic Insertion
              mps13TgTransgenic Insertion
                mps14TgTransgenic Insertion
                  ncv24TgTransgenic Insertion
                    1 - 10 of 13
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    No data available
                    Fish
                    No data available
                    Antibodies
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    AmCyanEFGAmCyan
                    DsRedEFGDsRed
                    EGFPEFGEGFP
                    GAL4FFEFGGAL4FF
                    mCherryEFGmCherry
                    NTREFGNTR
                    1 - 6 of 6
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                    Mapping
                    No data available