Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence
- University of Utah, United States
Abstract
Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and dependence on Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drives multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia towards distinct remodeling states and through Axl, alter microglial dependence on survival pathway, CSF1R.
Data availability
Sequencing data have been deposited in GEO under the reference series GSE192602.https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE192602Data generated or analyzed during this study are included in the manuscript.
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Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependenceNCBI Gene Expression Omnibus, GSE192602.
Article and author information
Author details
Jacqueline M Roberts
Funding
National Eye Institute (R01EY030307)
- Monica L Vetter
National Eye Institute (T32EY024234)
- Nathaniel Ghena
National Institute of Neurological Disorders and Stroke (T32NS115664)
- Nathaniel Ghena
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#18-08013 and #21-08001) of the University of Utah.
Copyright
© 2022, Anderson 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.
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Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence
eLife 11:e76564.
https://doi.org/10.7554/eLife.76564
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