William Talbot - US grants

DESCRIPTION (provided by applicant): In peripheral nerves, Schwann cells form myelin, which greatly accelerates axonal conduction. Myelination defects cause the symptoms of Charcot-Marie-Tooth disease and other peripheral neuropathies, but the mechanisms that regulate the formation of myelin remain unclear. Investigating the pathways that regulate Schwann cell myelination will lead to important advances in the understanding of peripheral nerve development and define mechanisms that can enhance remyelination after injury and in disease. The long-term goal of this project is to define the pathways that govern the formation of myelin in peripheral nerves. In the current funding period, we discovered that the orphan adhesion G protein coupled receptor (aGPCR) Gpr126 is essential for Schwann cells to initiate myelination. Like most adhesion GPCRs, the ligand that activates Gpr126 remains unknown. We have preliminary evidence that type IV collagen in the Schwann cell extracellular matrix binds Gpr126 and activates cAMP production in cultured cells expressing Gpr126. We also have preliminary evidence that purified type IV collagen stimulates cAMP production in purified rodent Schwann cells. We propose to test the hypothesis that type IV collagen acts as an endogenous activating ligand for Gpr126. Our specific aims are (1) to analyze the action of type IV collagen on rodent Schwann cells, and determine if the response to collagen requires Gpr126; (2) to analyze the function of type IV collagen genes in Schwann cell myelination in vivo; and (3) to analyze the functional effects of a variant in Gpr126 that is linked to a severe neurological deficit in human. These experiments will define the signals that activate Gpr126 signaling and myelination, lead to new insights into the role of the extracellular matrix in regulating myelination, and test the function of a Gpr126 variant linked to severe neurological disease in human.

Glia are non-neuronal cells with diverse functions that range from forming the myelin sheath to defending the brain against infection. A major goal of our research is to use the powerful experimental advantages of zebrafish to discover new genes that are essential for the development and function of two classes of glia in the CNS, oligodendrocytes and microglia. Oligodendrocytes form myelin on axons in the CNS. After an oligodendrocyte begins to myelinate axons, it has only a short developmental window (or ?critical period?) to extend new myelinating processes. Using genetic and cellular approaches in zebrafish, we have identified a number of positive and negative regulators of myelination. One of our goals is to determine how these factors control myelination during development, neural plasticity, and remyelination. In addition, we will investigate the molecular basis of the critical period. Microglia are highly motile, phagocytic glial cells in the CNS that destroy pathogens and clear debris such as apoptotic cells and damaged axons. Despite the importance of microglia in CNS health and disease, many critical questions remain to be addressed about these cells. We have conducted zebrafish mutational screens to discover essential microglial genes, and we are characterizing their functions using in vivo imaging and other approaches. The mechanistic insight gained from these studies will advance our fundamental understanding of the central nervous system, illuminate the pathways that are disrupted in diseases of the brain, and suggest avenues toward therapies for neurological disorders.