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Background Fluorescent reporter labeling and promoter-driven Cre-recombinant technologies have facilitated cellular investigations of physiological and pathological processes, including the widespread use of the  Cx3cr1   CreER-Eyfp/wt   mouse strain for studies of microglia. Methods Immunohistochemistry, Flow Cytometry, RNA sequencing and whole-genome sequencing were used to identify the subpopulation of microglia in  Cx3cr1   CreER-Eyfp / wt   mouse brains. Genetically mediated microglia depletion using  Cx3cr1   CreER-Eyfp/wt   Rosa26   DTA/wt   mice and CSF1 receptor inhibitor PLX3397 were used to deplete microglia. Primary microglia proliferation and migration assay were used for in vitro studies. Results We unexpectedly identified a subpopulation of microglia devoid of genetic modification, exhibiting higher  Cx3cr1  and CX3CR1 expression than  Cx3cr1   CreER-Eyfp/wt   Cre  +  Eyfp  +  microglia in  Cx3cr1   CreER-Eyfp / wt   mouse brains, thus termed  Cx3cr1  high  Cre  −  Eyfp  −  microglia. This subpopulation constituted less than 1% of all microglia under homeostatic conditions, but after Cre-driven DTA-mediated microglial depletion,  Cx3cr1  high  Cre   −   Eyfp  −  microglia escaped depletion and proliferated extensively, eventually occupying one-third of the total microglial pool. We further demonstrated that the  Cx3cr1  high  Cre   −   Eyfp  −  microglia had lost their genetic heterozygosity and become homozygous for wild-type  Cx3cr1 . Therefore,  Cx3cr1  high  Cre   −   Eyfp  −  microglia are  Cx3cr1   wt/wt   Cre   −   Eyfp  − . Finally, we demonstrated that CX3CL1–CX3CR1 signaling regulates microglial repopulation both in vivo and in vitro. Conclusions Our results raise a cautionary note regarding the use of  Cx3cr1   CreER-Eyfp/wt   mouse strains, particularly when interpreting the results of fate mapping, and microglial depletion and repopulation studies.

journal of neuroinflammation

An overlooked subset of Cx3cr1wt/wt microglia in the Cx3cr1CreER-Eyfp/wt mouse has a repopulation advantage over Cx3cr1CreER-Eyfp/wt microglia following microglial depletion