A phenotype-driven genetics screen identifies zinc finger protein 191 (Zfp191) as necessary for central nervous system myelination.

摘要

CNS myelination requires oligodendrocyte progenitor cells (OPCs) to migrate to their target axons where they mature into myelinating cells. Although a number of critical factors have been identified for these processes, our understanding of CNS myelination remains incomplete. The understanding of CNS myelination is important because myelin related diseases, such as multiple sclerosis (MS) and leukodystrophies, affect many people. In this study, we used a forward genetics approach to identify a mutant mouse characterized by an absence of CNS myelin despite the presence of normal numbers of process-extending premyelinating oligodendrocytes. Through linkage mapping we identified zinc finger protein 191 (Zfp191) as a gene necessary for the conversion of premyelinating oligodendrocyte into myelinating oligodendrocytes. Using in vivo and in vitro experimental strategies, we were able to determine that oligodendrocytes intrinsically require ZFP191 to properly differentiate and myelinate. This nuclear-localized protein belongs to a family whose members contain both DNA binding zinc finger domains and SCAN domains, which are responsible for protein-protein interactions. Although Zfp191 has not been associated with any human genetic disease, the mutant oligodendrocyte phenotype is similar to that of oligodendrocytes found within plaques of some MS patients, whose differentiation was disrupted at a premyelinating stage, resulting in a failure in remyelination. Very little is known about the mechanisms underlying the conversion of a premyelinating oligodendrocyte to a myelinating oligodendrocyte. Thus the study of this gene can potentially provide important insight into this feature of MS.