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A transgenic mouse model for inducible and reversible dysmyelination.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2000 Oct 15; Vol. 20 (20), pp. 7698-705. - Publication Year :
- 2000
-
Abstract
- 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-beta-delta-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.
- Subjects :
- Animals
Antigens, Differentiation biosynthesis
Blotting, Northern
Brain metabolism
Brain pathology
Demyelinating Diseases chemically induced
Demyelinating Diseases genetics
Disease Models, Animal
Female
Glial Fibrillary Acidic Protein biosynthesis
Gliosis pathology
Herpesvirus 1, Human genetics
In Situ Hybridization
Male
Mice
Mice, Transgenic
Myelin Basic Protein genetics
Myelin Sheath genetics
Myelin Sheath pathology
Oligodendroglia drug effects
Oligodendroglia pathology
Optic Nerve pathology
Optic Nerve ultrastructure
Promoter Regions, Genetic
RNA, Messenger drug effects
RNA, Messenger metabolism
Recombinant Fusion Proteins genetics
Sciatic Nerve pathology
Sciatic Nerve ultrastructure
Thymidine Kinase genetics
Arabinofuranosyluracil analogs & derivatives
Demyelinating Diseases metabolism
Myelin Sheath metabolism
Oligodendroglia metabolism
Recombinant Fusion Proteins metabolism
Thymidine Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 20
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 11027231