In the vertebrate nervous system, myelinating glia performs the spectacular feat of iteratively wrapping their membrane around axons to form the myelin sheath. Myelin allows for rapid nerve impulse propagation, and the glial cells that make myelin are also essential for neuronal health and survival. The importance of myelin is underscored in diseases in which it is disrupted, including multiple sclerosis, leukodystrophies, and numerous peripheral neuropathies. To date, no therapeutic strategies exist to halt demyelination or stimulate remyelination in disease or injury. As a vertebrate model organism that is amenable to both chemical and genetic screens, zebrafish represent the ideal system with which to dissect the molecular mechanisms that govern myelination. In a previous forward genetic screen, we discovered that the G protein-coupled receptor (GPCR) Gpr126 is essential for myelination in the peripheral nervous system, although the mechanisms by which Gpr126 functions are not completely understood. As a GPCR, Gpr126 represents an excellent potential therapeutic target to stimulate remyelination. To this end, we will define Gpr126-mediated pathways in glial development and myelination using both chemical and genetic screens in a hypomorphic gpr126 mutant, which generates reduced levels of myelin in the peripheral nervous system. (1) We will perform large-scale compound library screens to discover small molecules that can enhance or suppress the hypomorphic gpr126 mutant phenotype. (2) We will perform a forward genetic enhancer/suppressor screen of 2,000 genomes to define genetic modifiers of gpr126. Together, these experiments will define the mechanisms by which Gpr126 mediates myelination. Critically, these screens can also uncover new chemicals and genes that regulate glial cell development and myelination independently of Gpr126. These screens will enhance our understanding of the mechanisms that govern nervous system development and may point the way to novel therapeutics to promote nervous system repair in humans.
A major barrier of functional recovery in the nervous system is the lack of robust remyelination in injury or disease. Here, we propose to perform large-scale chemical and genetic modifier screens to uncover small molecules and mutations that can enhance or suppress a hypomorphic mutant allele of gpr126, which has reduced myelination in the peripheral nervous system. These screens will define both Gpr126-dependent and -independent mechanisms that govern myelination in the vertebrate nervous system.
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