Regulation of node of Ranvier formation and maintenance by astrocytes

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Proper nervous system function depends on interactions between neurons and non-neuronal glial cells. These neuron-glia relationships can be highly specific, such as the myelination of axons by oligodendrocytes. At the junctions between adjacent myelin sheaths, the nodes of Ranvier, complex structural components adhere the sheath to the axon membrane and constrain high densities of Na channels at the node in order to allow rapid saltatory conduction. Astrocytes, another glial cell, produce highly-ramified morphologies that effectively fill the space between all other cells to distribute nutrients and balance ion concentrations to provide an environment for neuronal communication. Nearly every node of Ranvier is covered by perinodal astrocyte processes (PAPs). While the neuron-oligodendrocyte interactions necessary for node of Ranvier structure and function have been extensively studied, the role of astrocytes at nodes and their interactions with oligodendrocytes' myelin sheaths are almost entirely unknown. While PAPs likely help maintain ion concentrations necessary for action potential generation, PAPs may serve additional functional and structural roles that could alter nodal size and excitability and even myelin sheath thickness. However, it remains unknown when astrocytes insert processes at the node and whether astrocytes contribute to the initial spacing of nodes during myelination onset, a factor that considerably shapes the speed and timing of action potential propagation. In addition to a potential role in establishing the pattern of myelination during development, PAPs may also contribute to the accuracy of remyelination. Following demyelination in diseases such as multiple sclerosis (MS), node of Ranvier ion channels and structural protein organization is disrupted, leading to action potential failure. However, some nodes of Ranvier are maintained throughout demyelination or reformed prior to remyelination, serving both as potential guideposts for newly generated myelin sheaths and maintaining action potential propagation in the absence of myelin. Enhancing this outcome would significantly impact functional recovery following a demyelinating attack in people with MS. In this proposal, essential astrocyte-oligodendrocyte interactions during node of Ranvier formation and the required astrocytic genetic factors will be identified. The unparalleled optical properties and genetic tools of the developing zebrafish will be used to visualize astrocyte process dynamics in vivo as myelin sheaths and nodes are created during development, and when they are disrupted during myelin sheath remodeling. Finally, critical genes governing these dynamics will be disrupted in astrocytes in a mouse model of MS to determine the extent to which these factors regulate node of Ranvier maintenance during remyelination. These experiments, lab environment, and additional training opportunities outlined in this proposal will present a phenomenal training experience that will enhance my technical skillset, further develop my knowledge of glial cell biology, and allow me to carve out a research area to lead as an independent investigator with my own laboratory.