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The Journal of Neuroscience, October 15, 2000, 20(20):7698-7705
A Transgenic Mouse Model for Inducible and Reversible
Dysmyelination
Carole
Mathis,
Colette
Hindelang,
Marianne
LeMeur, and
Emiliana
Borrelli
Institut de Génétique et de Biologie Moléculaire
et Cellulaire, Institut National de la Santé et de la Recherche
Médicale/Centre National de la Recherche
Scientifique/Université Louis Pasteur, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg,
France
Oligodendrocytes are glial cells devoted to the production of
myelin sheaths. Myelination of the CNS occurs essentially after birth. To delineate both the times of oligodendrocyte proliferation and
myelination, as well as to study the consequence of dysmyelination in vivo, a model of inducible dysmyelination was
developed. To achieve oligodendrocyte ablation, transgenic animals were
generated that express the herpes virus 1 thymidine kinase (HSV1-TK)
gene under the control of the myelin basic protein (MBP) gene
promoter. The expression of the MBP-TK transgene in oligodendrocytes is not toxic on its own; however, toxicity can be selectively induced by
the systemic injection of animals with nucleoside analogs, such as FIAU
[1-(2-deoxy-2-fluoro- - -arabinofuranosyl)-5-iodouracil]. This
system allows us to control the precise duration of the toxic insult
and the degree of ablation of oligodendrocytes in
vivo.
We show that chronic treatment of MBP-TK mice with FIAU during the
first 3 postnatal weeks triggers almost a total depletion of
oligodendrocytes in the CNS. These effects are accompanied by a
behavioral phenotype characterized by tremors, seizures, retarded
growth, and premature animal death. We identify the period of highest
oligodendrocytes division in the first 9 postnatal days. Delaying the
beginning of FIAU treatments results in different degrees of
dysmyelination. Dysmyelination in MBP-TK mice is always accompanied by
astrocytosis. Thus, this transgenic line provides a model to study the
events occurring during dysmyelination of various intensities. It also
represents an invaluable tool to investigate remyelination in
vivo.
Key words:
oligodendrocyte; inducible dysmyelination; transgenic; HSV1-TK; MBP promoter; CNS
Copyright © 2000 Society for Neuroscience 0270-6474/00/20207698-08$05.00/0
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