Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior
- Fred Hutchinson Cancer Research Center, United States
- Albert Einstein College of Medicine, United States
- University of Miami, United States
- The Rockefeller University, United States
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.
Data availability
All data generated in this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Simons Foundation Autism Research Initiative (New Investigator Award)
- Aakanksha Singhvi
American Federation for Aging Research (New Investigator Award)
- Aakanksha Singhvi
NIH Office of the Director (R35NS105094)
- Shai Shaham
NIH Office of the Director (NS114222)
- Aakanksha Singhvi
NIH Office of the Director (T32AG066574)
- Stephan Raiders
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Raiders et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,094
- views
-
- 622
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior
eLife 10:e63532.
https://doi.org/10.7554/eLife.63532
Further reading
-
- Cell Biology
Functional subpopulations of β-cells emerge to control pulsative insulin secretion in the pancreatic islets of mice through calcium oscillations.
-
- Cell Biology
Endosomes have emerged as major signaling hubs where different internalized ligand–receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane–actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.
