Adhesion GPCRs in myelination
A specific focus of our studies is to understand how adhesion G protein-coupled receptors (aGPCRs) control Schwann cell and oligodendrocyte development, myelination, and remyelination. We defined aGPCRs as key regulators of both PNS and CNS myelination by demonstrating that the aGPCR GPR126 is required in Schwann cells for many stages of Schwann cell development, while the aGPCR GPR56 controls oligodendrocyte precursor proliferation. Our work has also defined new ligands for GPR126 and activation paradigms for the aGPCR class. We are currently working to dissect the mechanisms by which GPR126 and GPR56 control myelinating glial cell development and myelin repair using zebrafish and mouse models.
Beyond GPR126 and GPR56, there are 31 other aGPCRs in the human genome – we are working to define the aGPCR repertoire required in myelinating glia during development and repair, how these aGPCRs are activated and how they signal in glia, and whether we can target aGPCRs to promote remyelination.
Genetic and Chemical Screens
Myelin is an evolutionary innovation of vertebrates; thus, zebrafish represents the simplest model system to elucidate the genetic and molecular mechanisms that regulate myelination. We recently completed a large-scale forward genetic screen and uncovered 28 new mutants with myelin defects in both the CNS and PNS. We are currently working to determine how these genes function in Schwann cells and oligodendrocytes using zebrafish and mouse models, and we expect that these studies will enhance our understanding of these critically important cells while pointing the way to novel therapeutics to promote regeneration in the nervous system.
In other studies, we are pursuing modifier screens to search in an unbiased way for modulators of GPR126 activity. We are performing small molecule and genetic screens to find compounds and mutations that can enhance or suppress hypomorphic gpr126 mutant phenotypes.
Both genetic screens are being performed in collaboration with other members of the Washington University Zebrafish Consortium.