Our long-term goal is to understand glial control of neuron receptive-ending shape and function. Neurons detect external stimuli through specialized dendritic receptive endings. Receptive-endings are malleable and regulate neuronal output. For example, neurons receive information at dendritic spines. Remodeling of spine shape occurs in development and is effected by experience. Perturbations in spine shape are associated with neurological disorders, suggesting that spine morphogenesis may play key roles in nervous system function. Like spines, receptive endings of sensory neurons are remodeled in development and by experience. Photoreceptor cell outer segments, for example, are turned over and rebuilt daily. Perturbation of sensory receptive-ending shape leads to sensory deficits and is a common pathology in sensory diseases. Despite clear clinical importance, the questions of how sensory cell shapes are regulated, how shape affects function, and how glia-neuron interactions control sensory neuron receptive-ending shape, have not been extensively addressed. The nematode C. elegans is an excellent organism in which to study glia-neuron interactions controlling sensory receptive-ending morphogenesis and plasticity. Sensory organ anatomy, physiology, and molecular biology are conserved from C. elegans to humans, making the nematode an exciting arena for revealing general principles of sensory organ development and function. The C. elegans AFD neuron mediates temperature sensation and cultivation-temperature memory. We showed that AFD receptive- ending shape is dynamically controlled and uncovered a novel signaling pathway guiding these changes. Shape changes require the receptor guanylyl cyclase GCY-8, controlling cGMP levels in AFD. High cGMP blocks receptive-ending extension, and this is overcome by overexpression of the actin regulator WASP-1. Loss of the glial transporter KCC-3, which specifically surrounds AFD, also blocks microvilli growth, by removing Cl- ions from an extracellular microdomain around AFD. Cl- ions function as novel direct inhibitors of GCY-8 cyclase activity. We further found that glia engulf and take up AFD neuron receptive-ending fragments, and that engulfment is required for AFD neuron function. Our results reveal glia-neuron interaction pathways determining neuron receptive-ending morphology, components of which are conserved in mammals. We propose three aims: (1) We will determine how glia form a unique microdomain around AFD neurons that is distinct from domains around other neurons. (2) We will study the role of glial FIG-1/thrombospondin in engulfment of AFD receptive endings and AFD neuron shape. (3) We will study the role of the phosphatidylserine receptor PSR-1 in engulfment of AFD endings and shape.
Our long-term goal is to understand how glial cells regulate the shapes and functions of neuron receptive endings. We recently showed that glia play a key role in regulating neuronal shape in the nematode C. elegans, and demonstrated a correlation between shape changes and behavior in this animal. Here we will test how glia control neuron shape changes by studying newly identified relevant glial components; our studies have broad implications for understanding neuron shape in all animals, including humans, particularly in the context of sensory organs.
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