Transcriptional control of CNS myelination in development and maturity.

Most oligodendrocytes (OLs) are formed in the early postnatal period but myelin-forming OLs continue to be born throughout healthy adult life, possibly contributing to learning and memory. New OLs are generated from proliferating oligodendrocyte precursors (OPs), which can also generate astrocytes and perhaps even neurons in some contexts. If we could understand the genetic mechanisms that control production of OPs and their differentiated progeny, we could use this knowledge to devise treatme nts for demyelinating and other neurodegenerative diseases. Towards this goal, we will investigate the transcriptional control of OP production and OL lineage progression during development and maturity. Our focus will be the Olig transcription factors, their post-transcriptional modifications and their modification-dependent activities and targets. We will also study myelin dynamics and its regulation during adulthood. Our aims are: A) to use mouse transgenesis to visualize adult myelin genesis and to gain clues to its regulation and functions. B) to determine how phosphorylation of Olig proteins alters their interactions with co-factors and gene targets and, by introducing Olig mutations into mice, how this orchestrates OL lineage progression during development and adulthood. C) to identify the signaling pathways that target Olig phosphorylation. D) to use this information to streamline OP production from induced pluripotent stem cells or somatic cells, for potential clinical application in the longer term.