Phosphorylation State of ZFP24 Controls Oligodendrocyte Differentiation

Myelin is a multilayer lipid membrane structure that ensheaths and insulates axons. In the central nervous system (CNS), myelin is formed by oligodendrocytes. During CNS development oligodendrocyte progenitor cells terminally differentiate into mature oligodendrocytes, produce myelin and wrap axons. The differentiation of oligodendrocytes and their expression of myelin protein genes are under tight transcriptional control. Zinc finger protein ZFP24, formerly known as ZFP191, is necessary for oligodendrocyte maturation and CNS myelination. We have demonstrated that ZFP24 binds to a consensus DNA sequence in proximity to genes important for oligodendrocyte differentiation and CNS myelination, and we have shown that this binding enhances target gene expression. We have also demonstrated that ZFP24 DNA binding is controlled by phosphorylation. Phosphorylated ZFP24, which does not bind DNA, is the predominant form in oligodendrocyte progenitor cells. As these cells mature into oligodendrocytes, the non-phosphorylated, DNA-binding form accumulates. We performed a large, unbiased screen and found that ZFP24 is phosphorylated by several isoforms of Protein Kinase C (PKC) and Calcium and Calmodulin dependent Kinase (CAMK). We also discovered that ZFP24 is dephosphorylated by the calcium and calmodulin dependent phosphatase Calcineurin. Using the Cuprizone model, we established that ZFP24 is important for CNS remyelination. In addition, we found that active, non-phosphorylated, ZFP24 is capable of inducing oligodendrocyte differentiation. Therefore, our studies provide potential therapeutic targets, the modulation of which might enhance the presence of the non-phosphorylated form of ZFP24 and the promotion of oligodendrocyte maturation and CNS remyelination.