An Inducible Genetic Tool To Track and Manipulate Specific Microglial States Reveals Their Plasticity and Roles in Remyelination

Authors

Kia M Barclay
Nora Abduljawad
Zuolin Cheng
Min Woo Kim
Lu Zhou
Jin Yang
Justin Rustenhoven
Jose A Mazzitelli
Leon C D Smyth
Dvita Kapadia
Simone Brioschi
Wandy Beatty
JinChao Hou
Naresha Saligrama
Marco Colonna
Guoqiang Yu
Jonathan Kipnis
Qingyun Li

Language

English

Publication Date

6-11-2024

Journal

Immunity

DOI

10.1016/j.immuni.2024.05.005

PMID

38821054

PMCID

PMC11299637

PubMedCentral® Posted Date

6-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative region-associated microglia (PAM) in developing white matter and disease-associated microglia (DAM) prevalent in various neurodegenerative conditions. PAM and DAM share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAM and DAM in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM and DAM gene expression. Through long-term tracking, we demonstrated microglial state plasticity. Lastly, we specifically depleted DAM in demyelination, revealing their roles in disease recovery. Together, we provide a versatile genetic tool to characterize microglial states in CNS development and disease.

Keywords

Microglia, Animals, Mice, Remyelination, Cell Plasticity, Demyelinating Diseases, Mice, Inbred C57BL, Mice, Transgenic, Disease Models, Animal, Brain, Myelin Sheath, White Matter, Microglia, Alzheimer’s Disease, Multiple Sclerosis, Development, Single-cell RNA Sequencing, Proliferative-Region Associated Microglia, Disease-Associated Microglia, Heterogeneity, Clec7a-CreER, Plasticity, Depletion

Published Open-Access

yes

Recommended Citation

Barclay, Kia M; Abduljawad, Nora; Cheng, Zuolin; et al., "An Inducible Genetic Tool To Track and Manipulate Specific Microglial States Reveals Their Plasticity and Roles in Remyelination" (2024). The Brown Foundation: Institute of Molecular Medicine. 40.
https://digitalcommons.library.tmc.edu/molecular_med/40