The shapes of neuronal receptive endings are exquisitely tuned to their function. Receptive endings of some sensory cells, including photoreceptors and auditory hair cells, have microvilli that allow dense packaging of receptors in a small space. To understand how sensory neurons form and maintain microvilli, we are studying the receptive endings of the C. elegans AFD thermosensory neuron, which are enveloped by the AMsh glia. Using cell ablations and inducible inhibition of secretion, we demonstrated that glia-secreted cues dynamically regulate the shape of AFD microvilli. To identify these glial signals, we performed a forward genetic screen seeking mutants with defects in AFD shape. Of the six mutants identified, we have cloned four. One mutant affects the gene unc-23, encoding a BAG2 co-chaperone that functions with Hsp70 to control protein folding. Microvilli defects in these mutants are progressive and coincident with the appearance of large vesicular structures within glia, suggestive of a secretory block. Intriguingly, mutations in human Hsp genes underlie a subset of sensory neuropathies characterized by progressive glial myelin damage and axonal tip degeneration. Our analyses lead us to propose a model where UNC-23 regulates protein folding of a small number of polypeptides in glia by antagonizing the E3/E4 ubiquitin ligase, CHIP/CHN-1. A second mutant we isolated affects the gene gcy-8, encoding an AFD-expressed receptor guanylyl cyclase important for thermosensation. Our analyses suggest that deregulated cyclase activity in AFD alters microvilli. Strikingly, receptor guanylyl cyclase mutations result in structurally abnormal microvilli in rod and cone cells of the eye. Finally, our preliminary data also suggest a role for the engulfment pathway in maintaining AFD microvilli. This is intriguing, given that engulfment by retinal pigmented epithelial cells sculpts rod and cone microvilli in mammals. Taken together, our studies provide new insight into how glia-neuron communication controls neuronal receptive ending morphology, and suggest that mechanisms governing receptive ending shape may be conserved.

Affiliation:
- The Rockefeller University, New York, NY 10065