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Quantifying the Heterogeneous Distribution of a Synaptic Protein in the Mouse Brain Using Immunofluorescence
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Published on: January 29, 2019

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Two distinct ontogenies confer heterogeneity to mouse brain microglia

Shrutokirti De1,2, Donn Van Deren1,3, Eric Peden1

  • 1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

Development (Cambridge, England)
|July 6, 2018
PubMed

Insights

Defective Hoxb8 microglia in mice cause compulsive behaviors. These Hoxb8 microglia originate from a distinct second wave of yolk sac hematopoiesis, unlike other 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.
Keywords:
AGM and fetal liver hematopoiesisFetal HSCsHoxb8 microgliaMicrogliaMicroglia ontogenyNon-Hoxb8 microgliaOCDObsessive-compulsive-spectrum disordersTmem119TrichotillomaniaYolk sac

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