Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Abstract

Glia in the central nervous system engulf neuron fragments to remodel synapses and recycle photoreceptor outer-segments. Whether glia passively clear shed neuronal debris, or actively prune neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here we report our discovery of glia-directed neuron pruning in C. elegans. Adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron by repurposing components of the conserved apoptotic corpse phagocytosis machinery. The phosphatidylserine (PS) flippase TAT-1/ATP8A, functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. This activates glial CED-10/Rac1 GTPase through the ternary GEF complex of CED-2/CrkII, CED-5/DOCK180, CED-12/ELMO. Execution of phagocytosis uses the actin-remodeler WSP-1/nWASp. This process dynamically tracks AFD activity and is regulated by temperature, the AFD sensory input. Importantly, glial CED-10 levels regulate engulfment rates downstream of neuron activity, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underlying glia-dependent engulfment in a peripheral sense-organ, and demonstrate that glia actively engulf neuron-fragments, with profound consequences on neuron shape and animal sensory behavior.

Ectocytosis prevents accumulation of ciliary cargo in C. elegans sensory neurons

“…Additionally, we could observe elongation and retraction of microvilli ( Video 9 ). This pruning of AFD microvilli was recently observed by Raiders et al, 2021 . We first asked whether pruning of AFD microvilli was strictly necessary to observe export of TSP-7-wrmScarlet from AFD to EVs in AMsh.…”

Sensory cilia act as a specialized venue for regulated extracellular vesicle biogenesis and signaling

“…35 Amphid glia engulf shed sensory endings of the ciliated AFD neuron and glia influence neuron shape and function. 36 Hence, environmental tip EVs and internal ciliary base EVs may have distinct functions in inter-organismal signaling 2,25,30,37 and neuron-glia communication, respectively. C. elegans EV-releasing cilia are specialized structurally and functionally.…”

Charging Up the Periphery: Glial Ionic Regulation in Sensory Perception

“…Analogously, the C. elegans sense-organ amphid sheath glia secretes the TSP-1 domain containing protein FIG-1 to modulate sensory neuron properties ( Bacaj et al, 2008 ). Vertebrate astrocytes use the MEGF10 and MERTK phagocytic pathway to mediate synapse elimination ( Chung et al, 2013 ), while Drosophila astrocytes similarly deploy the MEGF10 ortholog Draper to clear synaptic and neuronal debris following injury ( MacDonald et al, 2006 ; Hilu-Dadia and Kurant, 2020 ; Raiders et al, 2021b ) and C. elegans peripheral sense organ glia use a similar (albeit not identical) machinery to regulate sensory neuron shape and animal behavior ( Raiders et al, 2021a ).…”

“…Further, recent work from our laboratory has found that AMsh glia engulf fragments of AFD NRE in an activity dependent manner ( Raiders et al, 2021a ). Altering this glial pruning activity can alter NRE shape and associated animal behaviors post embryonic development, similar to ionic modulation by glial KCC-3.…”