PUBLICATION
Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs
- Authors
- Häberlein, F., Mingardo, E., Merten, N., Schulze Köhling, N.K., Reinoß, P., Simon, K., Japp, A., Nagarajan, B., Schrage, R., Pegurier, C., Gillard, M., Monk, K.R., Odermatt, B., Kostenis, E., Gomeza, J.
- ID
- ZDB-PUB-220922-3
- Date
- 2022
- Source
- Cell chemical biology 29(10): 1541-1555.e7 (Journal)
- Registered Authors
- Monk, Kelly, Nagarajan, Bhuvaneswari, Odermatt, Benjamin
- Keywords
- CNS, G-protein-coupled receptor, GPCR, GPR17, demyelinating disease, humanized animal model, oligodendrocyte, signal transduction, zebrafish
- MeSH Terms
-
- Animals
- Cell Differentiation
- Disease Models, Animal
- Humans
- Mammals/metabolism
- Nerve Tissue Proteins/metabolism
- Oligodendroglia*
- Prodrugs*/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Zebrafish/metabolism
- PubMed
- 36126653 Full text @ Cell Chem Biol
Citation
Häberlein, F., Mingardo, E., Merten, N., Schulze Köhling, N.K., Reinoß, P., Simon, K., Japp, A., Nagarajan, B., Schrage, R., Pegurier, C., Gillard, M., Monk, K.R., Odermatt, B., Kostenis, E., Gomeza, J. (2022) Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs. Cell chemical biology. 29(10):1541-1555.e7.
Abstract
Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches. Here we explore the experimental power of humanized zebrafish to foster the identification of pro-remyelination compounds via specific inhibition of GPR17. Using biochemical and imaging techniques, we visualize the expression of zebrafish (zf)-gpr17 during the distinct stages of oligodendrocyte development, thereby demonstrating species-conserved expression between zebrafish and mammals. We also demonstrate species-conserved function of zf-Gpr17 using genetic loss-of-function and rescue techniques. Finally, using GPR17-humanized zebrafish, we provide proof of principle for in vivo analysis of compounds acting via targeted inhibition of human GPR17. We anticipate that GPR17-humanized zebrafish will markedly improve the search for effective pro-myelinating pharmacotherapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping