Characterizing small leucine-rich proteoglycans as inhibitors of central nervous system axon regeneration

• Applicant: Dr. Daniel Wehner
• Subject Area: Developmental Biology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527729149

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in mammals, whereas it facilitates axon regeneration and functional recovery in the zebrafish. However, the molecular basis of these different fates is poorly understood. A number of scar constituents, including myelin-associated factors, basement membrane components, and chondroitin sulphate proteoglycans of the lectican proteoglycan family, have been identified to limit axonal regeneration in the mammalian CNS. However, removal of these factors has been reported to result in only modest regeneration, suggesting that key inhibitory molecules and mechanisms contributing to the regeneration failure remain to be discovered. Here, we propose to uncover interspecies differences in the ECM composition that contribute to the differential capacities of zebrafish and mammalian axons to regenerate after CNS injury. Our preliminary data identified the enrichment of small leucine-rich proteoglycans (SLRPs) as a prominent feature of rat and human CNS lesions, but not regeneration-competent zebrafish. Hence, we hypothesize that SLRPs represent previously unrecognized ECM factors that contribute to the axon growth-inhibitory properties of CNS scars. We further hypothesize that the absence of SLRPs is critical to shape the zebrafish spinal lesion site permissive to regeneration. The aim of this proposal is 1) to test whether increasing the abundance of candidate SLRPs in the zebrafish spinal lesion site impairs CNS regeneration, and 2) to elucidate the mechanisms mediating the growth-modulating properties of SLRPs. Overall, the proposed research project aims to functionally characterise SLRPs as novel ECM components of CNS scars that contribute to the differential regenerative capacity of mammalian and zebrafish CNS axons.

• DFG Programme: Research Grants