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Development. 2018 Jul 4;145(13). pii: dev152306. doi: 10.1242/dev.152306.

Two distinct ontogenies confer heterogeneity to mouse brain microglia.

Author information

1
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
2
Interdepartmental Program in Molecular Biology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
3
Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
4
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA mario.capecchi@genetics.utah.edu.

Abstract

Hoxb8 mutant mice show compulsive behavior similar to trichotillomania, a human obsessive-compulsive-spectrum disorder. The only Hoxb8 lineage-labeled cells in the brains of mice are microglia, suggesting that defective Hoxb8 microglia caused the disorder. What is the source of the Hoxb8 microglia? It has been posited that all microglia progenitors arise at embryonic day (E) 7.5 during yolk sac hematopoiesis, and colonize the brain at E9.5. In contrast, we show the presence of two microglia subpopulations: canonical, non-Hoxb8 microglia and Hoxb8 microglia. Unlike non-Hoxb8 microglia, Hoxb8 microglia progenitors appear to be generated during the second wave of yolk sac hematopoiesis, then detected in the aorto-gonad-mesonephros (AGM) and fetal liver, where they are greatly expanded, prior to infiltrating the E12.5 brain. Further, we demonstrate that Hoxb8 hematopoietic progenitor cells taken from fetal liver are competent to give rise to microglia in vivo Although the two microglial subpopulations are very similar molecularly, and in their response to brain injury and participation in synaptic pruning, they show distinct brain distributions which might contribute to pathological specificity. Non-Hoxb8 microglia significantly outnumber Hoxb8 microglia, but they cannot compensate for the loss of Hoxb8 function in Hoxb8 microglia, suggesting further crucial differences between the two subpopulations.

KEYWORDS:

AGM and fetal liver hematopoiesis; Fetal HSCs; Hoxb8 microglia; Microglia; Microglia ontogeny; Non-Hoxb8 microglia; OCD; Obsessive-compulsive-spectrum disorders; Tmem119; Trichotillomania; Yolk sac

PMID:
29973370
PMCID:
PMC6053660
DOI:
10.1242/dev.152306
[Indexed for MEDLINE]
Free PMC Article

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