More than trillions of nerve impulses are generated every second in our nervous system as part of the communication between neurons and their downstream targets. These electric signals, or action potentials, are propagated along the axons of neurons. In jawed vertebrates like us, many axons are wrapped in an insulating coating composed of compact glial membranes, called myelin. Myelination is one of the greatest evolutionary advances that facilitated the development of our complex nervous system. Myelin increases action potential conduction velocity while simultaneously decreasing energy and space demands. However, the breakdown of myelin in pathological or injury conditions disrupts nervous system function and causes a wide range of neurological deficits, including motor, sensory, and cognitive impairment. Our long-term research goal is to obtain a deep understanding of the molecular mechanisms of myelination and the biology of myelin-making glial cells--oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. This will provide essential pieces of information for developing therapeutic strategies to repair myelin and restore neurological functions in patients.

Rapid saltatory conduction requires the polarization of myelinated axons into distinct molecular domains. For example, paranodal junctions flank nodes of Ranvier at the gaps between myelin sheaths, and both nodes and paranodes contain molecular domains essential for proper functioning of myelinated axons. We recently discovered that an RNA-binding protein TDP-43 in myelinating glia regulates, through the repression of a cryptic exon, the expression of the cell adhesion molecule neurofascin, which is required for the assembly and maintenance of paranodal junctions. When TDP-43 is ablated in Schwann cells, neurofascin and paranodal junctions are lost, causing a 50% nerve conduction delay and motor deficits in mice. This revealed a previously unknown molecular link where the master gene regulator TDP-43 in Schwann cells regulates neuron-glia interactions and polarization of myelinated axons.

Rapid saltatory conduction also depends on the proper morphological parameters of myelin sheaths, including their thickness and length. We are currently investigating a special class of membrane-remodeling proteins, which participate in shaping oligodendroglial myelination.

Myelination is essential for proper nervous system function, and “proper” myelination is crucial for optimal nerve conduction and our daily activity, such as moving our body, sensing the world and making a decision. How is proper myelination achieved during development and through adaptive myelin remodeling by life experience? Understanding these mechanisms and knowing how to harness them will be required for manipulating glial cells to enhance and accelerate nervous system repair in the future.