Aakanksha Singhvi1,2,7, Shai Shaham3,7 and Georgia Rapti4,5,6,7 1Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA 2Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington 98195, USA 3Laboratory of Developmental Genetics, The Rockefeller University, New York, New York 10065, USA 4Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany 5Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory, Monterotondo, Rome 00015, Italy 6Interdisciplinary Center of Neurosciences, Heidelberg University, Heidelberg, Germany Correspondence: asinghvifredhutch.org; shahamrockefeller.edu; graptiembl.de

↵7 All authors contributed equally to this work.

The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia–neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology.