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 application 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. To test this hypothesis, we have formulated three specific aims.
In Aim 1, we will define the cell autonomous function of GPR56 in OL lineage development.
In Aim 2, we will study the role of GPR56 during CNS myelin repair. Our third and final Aim is to identify the ligand(s) that activates GPR56 during OL development and myelination. Our investigations will establish 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 and here, we propose to determine how the GPCR Gpr56 controls central nervous system myelination during development and myelin repair.
| Giera, Stefanie; Luo, Rong; Ying, Yanqin et al. (2018) Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. Elife 7: |
| Mehta, Paulomi; Piao, Xianhua (2017) Adhesion G-protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development. Dev Dyn 246:275-284 |
| Sigoillot, Séverine M; Monk, Kelly R; Piao, Xianhua et al. (2016) Adhesion GPCRs as Novel Actors in Neural and Glial Cell Functions: From Synaptogenesis to Myelination. Handb Exp Pharmacol 234:275-298 |
