Two distinct ontogenies confer heterogeneity to mouse brain microglia

Area of Science:

• Neuroscience
• Developmental Biology
• Hematopoiesis

Background:

• Hoxb8 mutant mice exhibit compulsive behaviors resembling human trichotillomania.
• Microglia are the sole Hoxb8 lineage-labeled cells in the mouse brain, implicating them in the disorder.
• The origin and development of microglia subpopulations remain incompletely understood.

Purpose of the Study:

• To investigate the source and developmental trajectory of Hoxb8 microglia.
• To determine if Hoxb8 microglia progenitors are distinct from canonical microglia.
• To explore the functional and distributional differences between Hoxb8 and non-Hoxb8 microglia.

Main Methods:

• Lineage tracing of Hoxb8 expressing cells in mice.
• Analysis of hematopoietic progenitor populations in yolk sac, aorta-gonad-mesonephros (AGM), and fetal liver during embryonic development.
• In vivo functional assays using Hoxb8 hematopoietic progenitor cells from fetal liver.
• Comparative molecular and functional analyses of Hoxb8 and non-Hoxb8 microglia.

Main Results:

• Two distinct microglia subpopulations were identified: canonical non-Hoxb8 microglia and Hoxb8 microglia.
• Hoxb8 microglia progenitors arise from a second wave of yolk sac hematopoiesis, distinct from the canonical wave.
• Hoxb8 progenitors are found in the AGM and fetal liver, expand significantly, and infiltrate the brain later (E12.5).
• Fetal liver-derived Hoxb8 hematopoietic progenitor cells can generate microglia in vivo.
• Despite molecular similarities and shared roles in brain injury response and synaptic pruning, Hoxb8 and non-Hoxb8 microglia exhibit distinct brain distributions and functional specializations.

Conclusions:

• Hoxb8 microglia originate from a separate developmental pathway compared to canonical microglia.
• The distinct origin and distribution of Hoxb8 microglia may underlie pathological specificity in disorders like trichotillomania.
• Non-Hoxb8 microglia cannot compensate for the loss of Hoxb8 function, highlighting critical functional differences between subpopulations.