The myelination of CNS axons during development and the remyelination of demyelinated axons in adults require 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 the molecular control of CNS myelination and remyelination remains incomplete. We have identified a zinc finger protein (Zfp191) that when mutated in mice results in the absence of CNS myelin despite the presence of normal numbers of mature, process-extending oligodendrocytes. Zfp191 mouse mutants express an array of myelin-related genes at significantly reduced levels, suggesting that this protein participates in the control of the CNS myelination program. Zfp191 belongs to a family of nuclear proteins whose members contain both DNA binding zinc finger domains and SCAN domains, which are responsible for protein-protein interactions. The goal of this proposal is to gain a better understanding of the role that Zfp191 plays in the myelination process. Zfp191 is expressed in all tissues and cell-types examined, including astrocytes and neurons, and the level of Zfp191 mRNA does not change as OPCs differentiate into mature, myelinating oligodendrocytes. Thus, a critical question that we will address in the studies outlined in this proposal is whether Zfp191 has a cell autonomous function in oligodendrocytes or whether other cell types contribute to the myelin abnormalities displayed by the Zfp191 mutants. Moreover, we will determine if the continued expression of this protein is required for the maintenance of the myelin sheath, and we will also assess if this protein has a similar essential function in the remyelination process. We will also explore the molecular mechanism by which ZFP191 controls the myelination program by determining its DNA and protein binding potential. Relevance: The studies described in this proposal will focus on the molecular control of the final stages of oligodendrocyte maturation, which result in the initiation of the myelination program. A better understanding of the factors that enhance oligodendrocyte maturation is essential in our effort to develop strategies to promote axonal remyelination in demyelinating neurological disorders (e.g. multiple sclerosis).
Remyelination following demyelinating insults, such as those that occur in multiple sclerosis patients, restores neuronal function and provides axonal protection. This proposal is focused on a gene (ZFP191) that we have identified in a forward genetics screen that appears essential for the final stages of oligodendrocyte maturation. The studies described are designed to further our understanding of the mechanism by which ZFP191 regulates the final stages of the myelination process.
|McKenzie, Andrew T; Moyon, Sarah; Wang, Minghui et al. (2017) Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer's disease. Mol Neurodegener 12:82|
|Elbaz, Benayahu; Traka, Maria; Kunjamma, Rejani B et al. (2016) Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS. Development 143:2356-66|
|Howng, Shen Yi B; Avila, Robin L; Emery, Ben et al. (2010) ZFP191 is required by oligodendrocytes for CNS myelination. Genes Dev 24:301-11|