Wan S Yang

Making motor axons grow

Centre for Neuroscience and Florey Neuroscience Institutes, The University of Melbourne, Australia Within the vertebrate central nervous system (CNS) the efficiency and speed of action potentials relies on myelin, a specialized membrane structure formed by oligodendrocytes. Proper establishment and maintenance of myelin is essential for the functioning of the CNS during both development and adult life, as evidenced by diseases such as the leukodystrophies and Multiple Sclerosis. In addition, ongoing myelination in the adult is thought to contribute to neural plasticity and learning. The regulation of myelination is thus a vital feature of both developmental and adult CNS processes. Recently, a number of regulatory mechanisms controlling myelination have been identified. At the extracellular level, these include a series of ligands expressed by neurons and astrocytes as well as neuronal activity itself. Within the oligodendrocyte lineage, recent advances have identified transcriptional and epigenetic pathways that are vital for the generation of myelinating cells. A significant current challenge to the field is to understand how these different levels of regulation interact with and influence each other. We have recently identified a previously uncharacterized transcription factor, Myelin Gene Regulatory Factor (MRF), which is specifically expressed within the brain by myelinating oligodendrocytes. MRF is vital for the process of CNS myelination during development; conditional knockout mice lacking MRF within the oligodendrocyte lineage generate oligodendrocyte progenitors and pre-myelinating oligodendrocytes however these oligodendrocytes are unable to express myelin genes or myelinate adjacent axons. Conversely, forced expression of MRF causes precocious expression of myelin proteins. We have demonstrated via ChIPSeq experiments that MRF acts directly at promoter and enhancer regions of genes encoding the protein components of myelin, as well as cytoskeletal, lipid metabolism and junctional proteins that underpin the myelination process. These findings establish MRF as a central point in the molecular events regulating myelination from which we may be able to understand how the other levels of regulation converge and interact.