Park Laboratory

Oligodendrocytes (OLs) differentiate to myelinate central nervous system (CNS). CNS myelination by OLs is important not only for saltatory conduction of action potentials but also for trophic support of nerve axons. An improved understanding of how the differentiation of OLs is regulated for CNS myelination should provide a firm basis on which to develop more effective therapeutics for demyelinating diseases.

Our current research efforts are focused on elucidating the transcriptional regulatory network controlling the differentiation of OLs. Over the past decade, application of genome-wide techniques has greatly facilitated the identification of new transcription factors that are important for CNS myelination. However, significant gaps in our knowledge remain regarding how they function at the molecular level. Also, there remain more transcription factors to be identified for the full elucidation of the transcriptional regulatory network. Thus, we are pursuing two different research directions at the moment.

The first direction is to elucidate the functional mechanism of Myrf, a key transcription factor for CNS myelination. Conditional knock-out mice in which Myrf is knocked out in the OL lineage cells completely fail to develop CNS myelin and exhibit severe neurological symptoms, eventually prematurely dying. Recently, we and the Emery laboratory have independently made the surprising discovery that Myrf is generated as an integral membrane protein that is auto-cleaved by its ICA domain into two fragments. This discovery invokes a number of intriguing questions about how Myrf drives the differentiation of OLs for CNS myelination.

The second direction is to identify new transcription factors for CNS myelination. By taking advantage of our computational expertise, we have predicted a number of new transcription factors for OL differentiation. We are currently characterizing them using primary OL cultures. Promising hits will be further analyzed by generating knock-out mice.