Regulation of oligodendrocyte differentiation and CNS myelination by a novel transmembrane transcription factor (345.4)

Abstract

Oligodendrocyte differentiation and the myelination of axons are crucial steps during vertebrate CNS development, allowing for the rapid saltatory conduction of action potentials. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf, previously known as MRF and GM98), that is vital for oligodendrocyte differentiation and the production of CNS myelin during development. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here, we find that that Myrf is a membrane‐associated transcription factor that, like Notch and the SREBPs, undergoes an activating proteolytic cleavage event to separate its transmembrane domain from the nuclear‐targeted N‐terminal region. Using ChIP‐Seq in oligodendrocytes we show that the N‐terminal cleavage product directly binds DNA, with Myrf binding sites strongly clustered around myelin genes. Luciferase assays confirm that these bound regions act as Myrf‐responsive enhancer regions. These findings identify Myrf as a novel transmembrane transcription factor, reconciling previous questions regarding its subcellular localization. We are currently investigating the expression and role of Myrf in human demyelinating disease and its animal models.