Cells in the nervous system are highly polarized and intercellular contacts take place at great distance from cell bodies. Oligodendrocytes produce numerous myelin sheaths on independent axons of variable size and physiology, which highlights remarkable flexibility in the production of myelin membrane at the tips of individual distal processes. Moreover, myelination is an activity-dependent process that enhances neuronal function and is required for learning and memory, indicating essential contributions of oligodendrocytes to neural circuit development. Interestingly, myelin deficiencies and altered myelin gene expression have been noted in Fragile X Syndrome, autism spectrum disorders, and a wide array of neurodevelopmental disorders, which indicate essential roles for oligodendrocytes in disease pathogenesis. Our recent evidence indicates that the RNA binding protein fragile x mental retardation protein (FMRP) is required for myelin sheath growth in a mechanism that is dependent on the translational regulation of mRNA. However, the genes coordinating initial myelin sheath growth are unknown, as are the subcellular mechanisms of mRNA regulation in oligodendrocytes. We hypothesize that FMRP regulates the localization and translation of mRNAs required for myelin sheath growth in oligodendrocytes. We will test this hypothesis using zebrafish, building upon our expertise in cell-type specific visualization and manipulation of gene expression in the developing nervous system. Our experimental plan has two parts. First, we will identify the precise location of FMRP binding on target mRNAs. Second, we will visualize the subcellular localization of mRNAs predicted to underlie myelin sheath growth and manipulate target gene expression specifically in oligodendrocytes of living zebrafish. This project has the potential to uncover the essential genes required for initial myelin sheath growth and will lay the foundation for future investigations into the mechanism of subcellular activity-dependent regulation of mRNA translation during myelination.
Oligodendrocytes are glial cells that wrap axons with myelin, a specialized membrane that can adapt to experience and enhance learning and cognition. However, myelination occurs at great distance from the glial cell body and the molecular mechanisms underlying the initial wrapping of axons are unknown. This project aims to identify the mechanisms of mRNA regulation that underlie initial myelin sheath growth in oligodendrocytes.
