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Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood

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Abstract

Whereas microglia involvement in virtually all brain diseases is well accepted their role in the control of homeostasis in the central nervous system (CNS) is mainly thought to be the maintenance of neuronal function through the formation, refinement, and monitoring of synapses in both the developing and adult brain. Although the prenatal origin as well as the neuron-centered function of cortical microglia has recently been elucidated, much less is known about a distinct amoeboid microglia population formerly described as the “fountain of microglia” that appears only postnatally in myelinated regions such as corpus callosum and cerebellum. Using large-scale transcriptional profiling, fate mapping, and genetic targeting approaches, we identified a unique molecular signature of this microglia subset that arose from a CNS endogenous microglia pool independent from circulating myeloid cells. Microglia depletion experiments revealed an essential role of postnatal microglia for the proper development and homeostasis of oligodendrocytes and their progenitors. Our data provide new cellular and molecular insights into the myelin-supporting function of microglia in the normal CNS.

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Acknowledgements

We thank Margarethe Ditter, Maria Oberle, Dr. Alexandra Müller, and Katrin Seidel for excellent technical assistance, Stefan Bohlen for the Imaris reconstructions, Antigoni Triantafyllopoulou for providing Nr4a1 −/− mice, Hauke Werner and Sandra Goebbels for providing NG2 YFP/WT mice, Peter Wieghofer for establishing microglia depleting experiments using BLZ945, Hans Christian Probst for providing Cd11c CreER mice, Mathias Jucker for the Ccr2 RFP/WT mice, and Jaclyn Wamsteeker Cusulin for critically reading and editing the manuscript. We apologize to colleagues whose work could not be cited because of space constraints. M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Sobek-Stiftung, the DFG (SFB 992, SFB1140, SFB/TRR167, Reinhart-Koselleck-Grant), the ERA-Net NEURON initiative “NEURO-IFN”, and the Sonderlinie Hochschulmedizin, project “neuroinflammation in neurodegeneration”. ESP and ERS are supported by NIH grant R01 NS091519.

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Authors and Affiliations

  1. Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany

    Nora Hagemeyer, Klara-Maria Hanft, Maria-Anna Akriditou, Ori Staszewski & Marco Prinz

  2. Molecular and Translational Neuroscience, Department of Neurology, Medical Faculty, Ulm University, Ulm, Germany

    Nicole Unger & Leda Dimou

  3. Physiological Genomics, Biomedical Center, Ludwig-Maximilians University, Munich, Germany

    Nicole Unger & Leda Dimou

  4. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    Eun S. Park & E. Richard Stanley

  5. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany

    Marco Prinz

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  1. Nora Hagemeyer
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  2. Klara-Maria Hanft
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  4. Nicole Unger
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  7. Ori Staszewski
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  8. Leda Dimou
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Contributions

NH designed and conducted the experiments. KH performed immunofluorescent analysis related to the cell number during development and proliferation. MAA performed analysis of electron microscope data. NU performed experiments with Sox10-iCreERT2 × CAG-eGFP mice and OPC cultures. ESP provided Csf1r −/− material. LD and ERS provided scientific input and edited the manuscript. OS analyzed the microarray data. NH and MP supervised the project and wrote the manuscript.

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Correspondence to Nora Hagemeyer or Marco Prinz.

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Electronic supplementary material

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401_2017_1747_MOESM1_ESM.jpg

Figure S1 (related to Fig. 1): High proliferation rate of postnatal microglia. (a) Scheme of experimental setup. Cx3cr1 GFP/Wt mice were intraperitoneally injected (i.p.) with 5-Ethynyl-2′-deoxyuridine (EdU) at P0-P3 or P4-P6. Analysis was performed on day P7, P10, and P21. (b) Quantification of EdU+/CX3CR1+ microglia in the corpus callosum, cortex, and cerebellum at the indicated time points. EdU was applied at P0-P3. Each symbol represents one mouse. Mean ± SEM are shown. (c) Quantification of EdU+/CX3CR1+ microglia in the corpus callosum, cortex, and cerebellum at the indicated time points. EdU was applied at P4-P6. Each symbol represents one mouse. Mean ± SEM are shown

401_2017_1747_MOESM2_ESM.jpg

Figure S2 (related to Fig. 1): Genes related to myelination and axogenesis are highly upregulated in the postnatal brain. (a)(b) Hierarchical clustering created on the most significantly differentially expressed genes (cut off adjusted to p value < 0.01) related to the GO-terms myelination and axogenesis between microglia from the corpus callosum and cortex at postnatal day 7 and at P42 (adult) (a) or between microglia from the corpus callosum and cortex only at postnatal day 7 (b). Heat map displays row z-score values from red to blue via white. (c) Immunofluorescent images of a P8 Cd11c CreER :R26-tomato mouse injected with tamoxifen at P3-P7. Representation of the accumulation of CD11c+ (red) Iba-1+ microglia (green) specifically in white matter regions (corpus callosum and cerebellum; indicated by arrows). Scale bar = 200 µm upper image, 50 µm: lower images

401_2017_1747_MOESM3_ESM.jpg

Figure S3 (related to Fig. 3): Purity of sorted microglia and oligodendrocyte progenitors. (a) Representative flow cytometry blots showing the sorting strategy for CD45+CD11b+ microglia (left) and PDGFRα+/NG2+ oligodendrocyte progenitors (OPCs; right) used for the gene expression analysis in (b). Cells were pre-gated on living cells, single cells, and Gr-1− cells. (b) Quantitative RT-PCR of the genes allograft inflammatory factor 1 (Aif1), integrin subunit alpha M (Itgam), adhesion G protein-coupled receptor E1 (Emr1), purinergic receptor P2Y12 (p2ry12), chondroitin sulfate proteoglycan 4 (Cspg4), platelet derived growth factor receptor alpha (Pdgfra), and SRY-Box 10 (Sox10). Data are normalized to Gapdh and β-Actin and presented normed to microglia. Bars represent mean ± SEM

401_2017_1747_MOESM4_ESM.jpg

Figure S4 (related to Fig. 3): Olig2 + oligodendrocyte numbers upon microglia depletion. Quantification of Olig2+ oligodendrocytes in the corpus callosum, cortex, and cerebellum at P8, 1 day after BLZ945-induced depletion of microglia at P2, P4, P6, and P7. n = 3 - 5; samples from two independent experiments. Significant differences were examined by an unpaired t test and marked with asterisks (*P < 0.05, **P < 0.01)

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Hagemeyer, N., Hanft, KM., Akriditou, MA. et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol 134, 441–458 (2017). https://doi.org/10.1007/s00401-017-1747-1

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