The DTA mouse model for oligodendrocyte ablation and CNS demyelination

Abstract

Genetic mouse models facilitate investigation of mechanisms underpinning human diseases and aid the development of novel therapeutic treatments. To better understand the demyelination and remyelination processes in adult-onset demyelinating diseases like multiple sclerosis (MS), we have developed the DTA mouse model system that allows for the widespread ablation of the mature oligodendrocytes, resulting in demyelination throughout the central nervous system (CNS). Induction of oligodendrocyte death in young adult DTA mice causes extensive CNS demyelination that leads to a severe neurological disease, followed by a full recovery that is associated with extensive replenishment of oligodendrocytes and remyelination. Thus, the DTA mouse enables investigation of the mechanisms that promote remyelination in MS and other adult-onset demyelinating diseases. Approximately 30 weeks later, the recovered DTA mice develop a fatal secondary demyelinating disease that is mediated by autoimmune T cells. Therefore, the DTA mouse model is also ideal for elucidating the role of oligodendrocyte death in eliciting autoimmunity in MS. In this chapter we describe the methods we used to generate the DTA mouse model and to analyze both the primary and secondary demyelinating diseases in DTA mice.