Recent reports have revealed that oligodendrocyte precursor cells (OPCs) are heterogeneous. It remains unclear whether such heterogeneity reflects different subtypes of cells with distinct functions or instead reflects transiently acquired states of cells with the same function. By integrating lineage formation of individual OPC clones, single-cell transcriptomics, calcium imaging and neural activity manipulation, we show that OPCs in the zebrafish spinal cord can be divided into two functionally distinct groups. One subgroup forms elaborate networks of processes and exhibits a high degree of calcium signaling, but infrequently differentiates despite contact with permissive axons. Instead, these OPCs divide in an activity- and calcium-dependent manner to produce another subgroup, with higher process motility and less calcium signaling and that readily differentiates. Our data show that OPC subgroups are functionally diverse in their response to neurons and that activity regulates the proliferation of a subset of OPCs that is distinct from the cells that generate differentiated oligodendrocytes.
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Raw sequence data, gene expression data and cell type annotation tables have been deposited in the Gene Expression Omnibus under accession number GSE132166. A web resource is available at https://ki.se/en/mbb/oligointernode. The data that support the findings of this study are available from the corresponding author upon reasonable request.
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We are grateful to R. Almeida, D. Lyons, T. Misgeld, M. Simons and all members of the Czopka laboratory for their comments and suggestions during the assembly of the data and their presentation in this manuscript. We thank B. Khakh (Department of Physiology, University of California, Los Angeles) for providing the CalEx plasmid before publication, K. Kwan (Department of Human Genetics, University of Utah) for providing the pME_nls-Cerulean and pME_nls-mApple plasmids, and D. Kim (Howard Hughes Medical Institute, Janelia Research Campus) for providing the GCaMP6m plasmid. We thank the Single Cell Genomics Facility, the Science for Life Laboratory, the National Genomics Infrastructure and UPPMAX for providing assistance with massive parallel sequencing and computational infrastructure. The bioinformatics computations were performed on resources provided by the Swedish National Infrastructure for Computing at UPPMAX, Uppsala University. E.A. is funded by the European Union (Horizon 2020 Research and Innovation Programme, Marie Skłodowska-Curie actions, grant SOLO, number 794689). Work in G.C.-B.’s research group was supported by the Swedish Research Council (grant 2015-03558), the European Union (Horizon 2020 Research and Innovation Programme, European Research Council Consolidator Grant EPIScOPE, grant 681893), the Swedish Brain Foundation (FO2017-0075), the Ming Wai Lau Centre for Reparative Medicine and the Karolinska Institutet. Work in T.C.’s research group was funded by a Starting Grant from the European Research Council (ERC StG MecMy, grant 714440), the Deutsche Forschungsgemeinschaft through its Emmy Noether Programme for young investigators (ENP CZ226/1-1) and the Deutsche Forschungsgemeinschaft Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy–D 390857198).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Confocal image of a Tg(olig1:memEYFP),Tg(olig1:nls-mApple) zebrafish at the level of the spinal cord at 21 d.p.f. (example of three animals from one experiment). Scale bar, 50 µm. b, Cross-sectional view of the spinal cord showing the distribution of myelin in Tg(mbp:EGFP-CAAX) at 7 d.p.f. (example of 12 animals from four experiments). Scale bar, 10 µm. c, Cross-sectional view of the spinal cord showing the distribution of pre- and postsynapses (Tg(elavl3:synaptophysin-RFP), anti-mCherry, anti-gephyrin) at 7 d.p.f. (example of 12 animals from four experiments). Scale bar, 10 µm. d, Confocal images of Tg(mbp:nls-EGFP),Tg(olig1:nls-mApple) transgenic animals between 4 and 28 d.p.f. (n values as in e). Scale bar, 20 µm. e, Cell numbers of OPCs (olig1: nls-mApple-positive, mbp:nls-EGFP-negative) and myelinating oligodendrocytes (mbp:nls-EGFP-positive) in the spinal cord. Data are expressed as mean cells per field ± s.d. at 3 (n = 17 animals in two experiments), 5 (n = 15 animals in three experiments), 7 (n = 15 in three experiments), 10 (n = 16 in three experiments), 13 (n = 17 in two experiments), 16 (n = 17 in two experiments), 20 (n = 20 in three experiments), 24 (n = 12 in three experiments) and 28 (n = 13 in three experiments) d.p.f. f, Example images of individual OPCs showing a range of morphologies. The soma can be localized within axo-dendritic (top) or neuron-rich areas (middle, bottom). The process network of an individual cell can be restricted to one side of the spinal cord (top and middle cells), but it can also reach to both sides of the spinal cord (bottom cell) (n values as in g). Scale bar, 10 µm. g, OPC morphometry using three-dimensional process tracing and creation of a volume hull around the reconstructed filaments (n = 228 cells from 56 animals between 3 and 16 d.p.f. in 24 experiments). Scale bar, 10 µm.
a, Schematic overview of cell isolation, sorting and sequencing. b, Flow cytometry plots of olig1:memEYFP-sorted cells and wild-type control cells. Dotted lines indicate the gating used (example from two independent experiments). c, t-SNE plot showing expression of sox10 (total sample size n = 310 cells). Immunohistochemistry for sox10 on transverse spinal cord sections of 7 d.p.f. Tg(olig1:nls-mApple),Tg(mbp:nls-EGFP) animals and quantification of sox10-expressing OPCs (olig1:nls-mApple-positive, mbp:nls-EGFP-negative) in neuron-rich and axo-dendritic areas (100% (68/68) versus 100% (49/49) positive cells, n = 16 animals in four experiments). Dotted lines indicate the outlines of the spinal cord. Scale bar,10 µm. d, t-SNE plot showing expression of olig2 and nkx2.2a (sample size as in c). e, t-SNE plot showing expression of ppp1r14bb, mbpa and plp1a (sample size as in c). f, Confocal images with in situ hybridizations for cspg4, gpr17, myrf, and labeling of EDU incorporated cells on transverse spinal cord sections of 7 d.p.f. Tg(olig1:nls-mApple),Tg(mbp:nls-EGFP) animals (see Fig. 2e,i,k,l for respective n values). Scale bar, 10 µm.
Quantification of OPC complexity and soma position from imaging timelines between 3 and 15 d.p.f. Measured is the last timepoint as OPC before differentiation, as assessed by myelin sheath formation (imaging intervals of 1 d between 3 and 7 d.p.f., and 2 d between 7 and 15 d.p.f.). n = 10, n = 6, n = 3, n = 3, n = 3, n = 2, n = 1, n = 2, n = 2, n = 2, n = 1, n = 5 and n = 1 cells at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 d.p.f. Data from 23 animals in six experiments.
a, Overview images of transgenic zebrafish labeling nuclei of OPCs (olig1:nls-mApple) and myelinating oligodendrocytes (mbp:nls-EGFP) at the beginning and end of a timelapse between 3 and 5 d.p.f. Dashed boxes indicate the areas shown in panel c (n = 3 animals in two experiments). Scale bar, 10 µm. b, Quantification of the fates of OPCs found in neuron-rich areas. A detailed breakdown of the data shown in Fig. 4e. c, Zoom-ins and false coloring of the time-lapse in a, showing potential behaviors of OPCs in neuron-rich areas: remaining quiescent (red cell), generating new OPCs in neuron-rich areas (magenta cells) or generating new OPCs in axo-dendritic areas (green cells). The insets at the first and last timepoints show the absence of myelin markers (mbp:nls-EGFP) in the cells studied (n = 3 animals in two experiments). Scale bar, 10 µm.
a, Time series of an individual OPC with its soma in neuron-rich areas that gives rise to myelinating oligodendrocytes by proliferation-mediated generation of daughter OPCs in axo-dendritic areas. Left panel, confocal images. Middle panel, reconstructions of the starting cell and the individual daughter cells. Cells that will differentiate are shown in blue. Right panels, y-axis rotations showing olig1:nls-mApple cell body positions within the hemi-spinal cord. Dashed lines depict the outline of the spinal cord. One of eight examples from seven animals in six experiments. Scale bar, 10 µm. b, Graphical summary of cell fates from the data analyzed in Fig. 5a–d. See also Supplementary Fig. 2.
a, Example images of individual olig1:GCaMP-CAAX-labeled OPCs in axo-dendritic areas of the zebrafish spinal cord at 4 d.p.f. The absence of nascent ensheathments indicates that these cells are not early differentiating oligodendrocytes (n = 9 independent experiments). Scale bar, 10 µm. b, Dorsal views of Tg(olig1:GCaMP6m),Tg(mbp:KillerRed) transgenic zebrafish at 4 d.p.f. to label OPCs and differentiated oligodendrocytes. Dotted box indicates position of zoom-ins in bottom row (n = 3 animals in one experiment). Scale bars, 50 µm (top) and 20 µm (bottom). c, Quantification of single- and double-positive cells from images as shown in b. d, ∆F/F0 GCaMP transients of individual cells in two Tg(olig1:GCaMP6m) zebrafish. Green traces depict cells in axo-dendritic areas, and gray traces depict cells in neuron-rich areas (total of eight animals in eight experiments).
a, Minimum intensity projections of a 2 min time-lapse of fish freely swimming in a 3 cm petri dish in different treatment conditions (n = 6, n = 7, n = 3 and n = 3 animals in control, 4-AP, TTX and 4-AP+TTX conditions, three independent experiments). b, Traces of GCaMP transients from Tg(elavl3:h2b-GCaMP6s) zebrafish at 4 d.p.f. and after overnight incubation in 0.1 mM 4-AP and before and after 10 µM TTX (seven animals per condition in two experiments). c, Confocal images of Tg(mfap4:memCerulean),Tg(olig1:nls-mApple) zebrafish at 4 d.p.f. after treatment with 0.1 mM 4-AP, 0.5 mM 4-AP, or Danieau’s solution as a control. Transmitted light images show spinal cord morphology and tissue integrity after drug treatment. Scale bars, 100 µm. The graph shows the number of macrophages that accumulate in a 400 µM length of spinal cord of Tg(mfap4:memCerulean) zebrafish after 1 d of control (2 ± 0.25/2 cells), 0.1 mM (2 ± 1/2 cells) and 0.5 mM (3 ± 0.25/2 cells) 4-AP treatment (median ± 25%/75% percentiles). P = 0.43 (control versus 0.1 mM 4-AP), P = 0.03 (control versus 0.5 mM 4-AP), Kruskal–Wallis test, test statistic=3.003, n = 16, n = 19 and n = 8 animals in three experiments. d, Representative images of Tg(mbp:nls-EGFP),Tg(olig1:nls-mApple) zebrafish in control treatment and after 2 d of 0.1 mM 4-AP treatment (see Fig. 7e for n values). Scale bar, 20 µm.
Supplementary Figures 1 and 2, Supplementary Tables 1–3.
Pan and zoom of OPC reporter lines. Transgenic olig1:memEYFP, olig1:nls-Cerulean zebrafish at 5 d.p.f. showing the distribution of OPCs and their process network within the CNS. Representative images from four animals in two independent experiments.
Segmentation of individual OPCs. Animation of process tracing and hull construction to reconstruct single OPCs at 4 d.p.f. in the spinal cord (example of n = 76 cells from 23 animals in 11 experiments).
Time-lapse of process remodeling of an OPC within axo-dendritic areas. 60 min time-lapse of individual OPC within axo-dendritic areas of the spinal cord recorded at 5 min intervals (n = 4 cells from four animals in four experiments). See also Supplementary Video 4.
Time-projection of process remodeling of an OPC within axo-dendritic areas. Projection of a 60 min time-lapse of an individual OPC within axo-dendritic areas of the spinal cord. Stable processes are green, and remodeled processes appear in magenta (n = 4 cells from four animals in four experiments).
Time-lapse of process remodeling of an OPC with its soma in neuron-rich areas. 60 min time-lapse of an individual OPC with its soma in neuron-rich areas of the spinal cord recorded at 5 min intervals (n = 4 cells from four animals in four experiments). See also Supplementary Video 6.
Time-projection of process remodeling of an OPC with its soma in neuron-rich areas. Projection of a 60 min time-lapse of an individual OPC with its soma in neuron-rich areas of the spinal cord. Stable processes are green, and remodeled processes appear in magenta (n = 4 cells from four animals in four experiments).
Behavior and fate of individual OPC with its soma in neuron-rich areas. 24 h time-lapse showing a cell division of an individual OPC with high process complexity typically found when the OPC soma resides in neuron-rich areas (n = 13 cells from four animals in three experiments).
Behavior and fate of an individual OPC within axo-dendritic areas. 13 h time-lapse showing differentiation of an individual OPC with low process complexity typically found residing in axo-dendritic areas (n = 21 cells from nine animals in seven experiments).
Transition of OPC soma between neuron-rich and axo-dendritic areas is linked to cell divisions. 42 h timelapse of olig1:nls-mApple-labeled OPCs. The rounded nucleus shaded in green represents an OPC residing in neuron-rich areas. It divides to give rise to a daughter cell in axo-dendritic areas (elliptic nucleus), and the daughter cell continues to divide. Representative results from three animals in two independent experiments.
OPC calcium transients can be restricted to process subdomains. Time-lapse of two olig1-GCaMP6m-CAAX-labeled OPCs showing transients in process subdomains. Example of 27 animals in 23 independent experiments.
OPC calcium transients can spread throughout the cell. Time-lapse of two olig1-GCaMP6m-CAAX-labeled OPCs where one cell shows transients throughout the cell. Example of 27 animals in 23 independent experiments.
Population analysis of OPC calcium transients. Time-lapse of a Tg(olig1:GCaMP6m) at the level of the spinal cord (dorsal view) showing a GCaMP transient in the soma of a single OPC within the population. Example of eight animals in eight independent experiments.
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Marisca, R., Hoche, T., Agirre, E. et al. Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation. Nat Neurosci 23, 363–374 (2020). https://doi.org/10.1038/s41593-019-0581-2
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