Myelin is the multilayered membrane generated by glial cells that insulates and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. The molecular mechanisms that govern oligodendrocyte development, myelination, and myelin repair are poorly understood; myelin is disrupted in many neurological diseases, and so a better understanding of OL biology has important clinical implications. The object of this proposal is to study how the adhesion G protein- coupled receptor GPR56 regulates OL development, myelination, and myelin repair. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), in which the normal cortical folds of the cerebrum are replaced by numerous small gyri. In addition to the poor formation of the cerebral cortex, white matter is also adversely affected in BFPP patients. MRI images of BFPP brains reveal signal changes indicating myelination defects. Furthermore, our preliminary studies demonstrate that: 1) GPR56 is expressed in oligodendrocyte progenitor cells (OPCs) and immature OLs; 2) disruption of Gpr56 leads to CNS myelin defects in mice; and 3) there is a novel putative ligand of GPR56 in CNS. Taken together, our data support the hypothesis that GPR56 is a previously unappreciated regulator of myelination in the CNS. This proposal is designed to test this hypothesis, thus establishing novel regulators of glial cell development and myelination. Our work is likely to enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in myelin disease.
The myelin sheath surrounding axons is essential for the proper function of the nervous system. Its disruption causes many devastating diseases including multiple sclerosis. There is a pressing need for therapies that can prevent demyelination or stimulate remyelination in these diseases, as no current treatments exist to inhibit degeneration or promote regeneration. G protein coupled-receptors (GPCRs) are excellent therapeutic targets. Members of the family of adhesion GPCRs are important in regulating myelin formation by mediating cell and extracellular matrix interaction. Here, we propose to determine how adhesion GPCRs controls central nervous system myelination during development and myelin repair.
