A transgenic mouse model for inducible and reversible dysmyelination

Oligodendrocytes are glial cells devoted to the production of myelin sheath s. 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 dysmy elination was developed. To achieve oligodendrocyte ablation, transgenic an imals 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 o n its own; however, toxicity can be selectively induced by the systemic inj ection of animals with nucleoside analogs, such as FIAU [1-(2-deoxy-2-fluor o-beta-delta-arabinofuranosyl)5-iodouracil]. This system allows us to contr ol the precise duration of the toxic insult and the degree of ablation of o ligodendrocytes 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 th e CNS. These effects are accompanied by a behavioral phenotype characterize d by tremors, seizures, retarded growth, and premature animal death. We ide ntify the period of highest oligodendrocytes division in the first 9 postna tal days. Delaying the beginning of FIAU treatments results in different de grees of dysmyelination. Dysmyelination in MBP-TK mice is always accompanie d by astrocytosis. Thus, this transgenic line provides a model to study the events occurring during dysmyelination of various intensities. It also rep resents an invaluable tool to investigate remyelination in vivo.