An inducible genetic tool for tracking and manipulating specific microglial states in development and disease

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 and other functional properties. 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 report the generation of an inducible Cre driver line, Clec7a-CreERT2, designed to target PAM and DAM in the brain parenchyma. Utilizing this tool, we profile labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM/DAM gene expression. Through long-term tracking, we demonstrate surprising levels of plasticity in these microglial states. Lastly, we specifically depleted DAM in cuprizone-induced demyelination, revealing their roles in disease progression and recovery.