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

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in 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 proteoglyc...

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Published inbioRxiv
Main Authors Kolb, Julia, Nora, John, Kim, Kyoohyun, Möckel, Conrad, Rosso, Gonzalo, Möllmert, Stephanie, Kurbel, Veronika, Parmar, Asha, Sharma, Gargi, Beck, Timon, Müller, Paul, Schlüßler, Raimund, Frischknecht, Renato, Wehner, Anja, Krombholz, Nicole, Steigenberger, Barbara, Blümcke, Ingmar, Singh, Kanwarpal, Guck, Jochen, Kobow, Katja, Wehner, Daniel
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.11.2022
Subjects
Central nervous system
Danio rerio
Extracellular matrix
Lesions
Mechanical properties
Proteoglycans
Recovery of function
Regeneration
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Summary:Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in 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 causal factor in regeneration failure. We demonstrate that the SLRPs Chondroadherin, Fibromodulin, Lumican, and Prolargin are enriched in 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 structural and mechanical properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as previously unknown inhibitory ECM factors in the human CNS that impair axon regeneration by modifying tissue mechanics and structure.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2022.11.21.517128