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Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing

Qingyun Li, Zuolin Cheng, Lu Zhou, Spyros Darmanis, Norma Neff, Jennifer Okamoto, Gunsagar Gulati, Mariko L. Bennett, Lu O. Sun, Laura E. Clarke, Julia Marschallinger, Guoqiang Yu, Stephen R. Quake, Tony Wyss-Coray, Ben A. Barres

Preprint posted on September 01, 2018 https://www.biorxiv.org/content/early/2018/09/01/406363

Cells that shape the brain: transcriptomic analysis of developing microglia identifies a transient subpopulation that may regulate CNS myelination

Selected by Zheng-Shan Chong

Background

Microglia are the resident macrophage population in the brain and have been implicated in a variety of developmental disorders including autism and schizophrenia. They are known to arise early on in development from early yolk sac progenitors whilst other tissue-resident macrophages derive from hematopoietic stem cells [1]. However, other aspects of microglia development in terms of temporal and spatial changes are less well understood.  In this study, Qingyun Li and colleagues from the late Ben Barres’ lab explore microglial development through single-cell transcriptomics.

 

Key findings

Using single-cell RNA sequencing of microglia from embryonic (E14.5), postnatal (P7) and adult (P60) mice, Li et al uncovered a subset of postnatal microglia which resembled degenerative disease-associated microglia (DAM). These microglia are characterised by decreased levels of microglial homeostatic gene expression, and concomitant upregulation of DAM-associated genes. To determine the distribution of this population of microglia, they used RNA in situ labelling of marker genes to show that DAM-like microglia are expressed almost exclusively in the corpus callosum and cerebellar white matter, thus naming them white matter associated microglia (WAMs). By tracking the appearance of WAMs over the course of development, they demonstrate that WAMs appear transiently between P4 and P14 (peaking at P7), and have different morphology from cortical microglia. They also show that WAMs are highly phagocytic and interact extensively with newly formed oligodendrocytes, suggesting that this transient subpopulation of microglia may be responsible for phagocytosing oligodentrocytes during CNS myelination, which coincides with the appearance of WAMs.

 

Why is it important?

Firstly, this study provides a high quality, multi-dimensional dataset of microglia at different developmental timepoints, which the authors made available through their brain RNA-seq website www.brainrnaseq.org. In addition, the discovery of a transient and spatially distinct subset of microglia potentially involved in regulating proper CNS myelination could have implications for understanding the mechanisms through which microglia influence developmental disorders.

 

Questions arising:

This finding raises many questions about the regulation of this subset of microglia. Is the DAM-like phenotype intrinsically driven by genetic programs or extrinsically driven by signalling molecules in white matter? What causes the population to disappear by postnatal day 14, and what signals may modulate their phagocytic activity?

 

A question regarding the therapeutic relevance: how closely does the activity of DAMs resemble WAMs?

 

Lastly, the authors don’t comment that much on the data from embryonic microglia. What transcriptional programs are active in those cells? How does transcriptional heterogeneity in embryonic microglia compare to postnatal and adult microglia?

 

References

[1] Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., … Merad, M. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330(6005), 841–845.

 

Posted on: 24th September 2018

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