Abstract During development, cells adhere to specific partners in precise arrangements to build well-ordered structures. Nowhere is this more impressive than in the brain, which has the most diverse cell types with the most elaborate morphologies and most highly specific connectivity of any organ. While extensive work has been done to identify mechanisms of partner selection among neurons, far less is known about neuron-glia pairing. Glia extend membranous processes that intimately wrap specific synapses, affecting synapse growth and pruning, and modulating synapse strength during learning. Defects in glia-neuron interactions are associated with a host of neurodevelopmental disorders. Thus, understanding how specific neuron-glia attachments are determined will shed light on a key aspect of brain wiring, and will reveal general principles by which cells select specific adhesion partners during development. This project uses a single defined neuron-glia attachment as a model to identify the developmental and genetic mechanisms that underlie neuron-glia pairing. It focuses on a single C. elegans sensory neuron, called URX, that forms membranous attachments to a specific glial partner, the lateral ILso glial cell. Highly cell-type-specific drivers allow this single, defined neuron-glia contact to be visualized or genetically manipulated in live intact animals. Preliminary data show that this specific neuron-glia attachment arises in embryos by a multi-step developmental process. First, the URX dendrite anchors to a 'guidepost' glial cell during embryo elongation, positioning the dendrite ending at the nose tip. Then, a sensory cilium grows out of the dendrite tip to form the elaborate attachment to the ILso glial partner. This project will investigate: Aim 1. How does the dendrite anchor to the guidepost cell? Preliminary data suggest that epithelial adherens junctions are modified to create the anchoring site. Aim 2. How does the sensory cilium mediate neuron-glia adhesion? Preliminary genetic screens have identified several mutants that disrupt cilia adhesion, including one that affects a proteoglycan with homology to a protein that mediates glia-synapse interactions in mammalian brain. Aim 3. What is the function of this highly specific neuron-glia attachment? Preliminary work indicates that the attachment undergoes experience-dependent remodeling, suggesting a mechanism by which glia could tune the sensitivity of the neuron by altering the physical structure of its receptive ending.