Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs

Felix Häberlein, Enrico Mingardo, Nicole Merten, Nina Katharina Schulze Köhling, Philip Reinoß, Katharina Simon, Anna Japp, Bhuvaneswari Nagarajan, Ramona Schrage, Cecile Pegurier, Michel Gillard, Kelly R. Monk, Benjamin Odermatt, Evi Kostenis, Jesus Gomeza

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1541-1555
Number of pages15
JournalCell Chemical Biology
Volume29
Issue number10
DOIs
StatePublished - Oct 20 2022

Keywords

  • CNS
  • demyelinating disease
  • G-protein-coupled receptor
  • GPCR
  • GPR17
  • humanized animal model
  • oligodendrocyte
  • signal transduction
  • zebrafish

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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