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Mult Scler. 2017 Jul 1:1352458517721355. doi: 10.1177/1352458517721355. [Epub ahead of print]

The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.

Author information

1
Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, ICM-GH Pitié-Salpêtrière, and IBPS F-75013 Paris, France.
2
Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, APHP, Institut du Cerveau et de la Moelle épinière (ICM), GH Pitié-Salpêtrière, Paris, France.
3
CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris, France.
4
Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, APHP, ICM-GH Pitié-Salpêtrière, Paris, France; Department of Neurology, School of Medicine, Yale University, New Haven, CT, USA.
5
Watchfrog, Evry, France.
6
CNRS UMR 7196, Muséum National d'Histoire Naturelle, Paris, France.

Abstract

BACKGROUND:

In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

OBJECTIVE:

A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

METHODS:

In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin. Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.

RESULTS:

Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.

CONCLUSION:

This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

KEYWORDS:

Crispr/Cas9; Multiple sclerosis; Xenopus laevis; demyelination; gene editing; oligodendrocyte; remyelination; transgenic

PMID:
28752787
DOI:
10.1177/1352458517721355

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