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Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division

Nature Neuroscience volume 17, pages 1518–1527 (2014)Cite this article

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Abstract

Oligodendrocytes in the mammalian brain are continuously generated from NG2 cells throughout postnatal life. However, it is unclear when the decision is made for NG2 cells to self-renew or differentiate into oligodendrocytes after cell division. Using a combination of in vivo and ex vivo imaging and fate analysis of proliferated NG2 cells in fixed tissue, we demonstrate that in the postnatal developing mouse brain, the majority of divided NG2 cells differentiate into oligodendrocytes during a critical age-specific temporal window of 3–8 d. Notably, within this time period, damage to myelin and oligodendrocytes accelerated oligodendrocyte differentiation from divided cells, and whisker removal decreased the survival of divided cells in the deprived somatosensory cortex. These findings indicate that during the critical temporal window of plasticity, the fate of divided NG2 cells is sensitive to modulation by external signals.

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Figure 1: Temporal dynamics of oligodendrocyte differentiation after NG2 cell division in vivo.
Figure 2: NG2cre:ZEG:PLPDsRed triple-transgenic mice identify cells at distinct stages of oligodendrocyte differentiation.
Figure 3: Longitudinal in vivo imaging of cortical NG2 cells.
Figure 4: In vivo imaging of oligodendrocyte differentiation.
Figure 5: The temporal dynamics of oligodendrocyte differentiation are altered by myelin damage.
Figure 6: Whisker deprivation reduces oligodendrocyte generation in the somatosensory cortex.
Figure 7: Whisker sensory deprivation increases apoptosis of divided NG2 cells.

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Acknowledgements

This work was funded by grants from the US National Multiple Sclerosis Society (RG41579 to A.N.), the US National Institutes of Health (NIH R01NS073425 to A.N. and NIH R01AG27855 to J.G.) and the US National Science Foundation (A.N.). We thank F. Kirchhoff (University of Saarland) for providing PLPDsRed transgenic mice, K. Ikenaka (National Institute for Physiological Science, Japan) for the DM20/PLP antibody, M. Nedergaard for initial training with in vivo imaging experiments, and Y. Sun for assistance in maintaining the transgenic mouse colony.

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Authors and Affiliations

  1. Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

    Robert A Hill, Kiran D Patel, Christopher M Goncalves & Akiko Nishiyama

  2. Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA

    Robert A Hill & Jaime Grutzendler

  3. Connecticut Stem Cell Institute, University of Connecticut, Farmington, Connecticut, USA

    Akiko Nishiyama

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Contributions

R.A.H. designed, conducted and analyzed EdU pulse chase, live imaging and whisker ablation experiments, and wrote the manuscript. K.D.P. performed and analyzed EdU labeling and cell death experiments. C.M.G. performed a portion of EdU pulse chase labeling in P21 mice. J.G. supervised in vivo imaging and provided input on the manuscript. A.N. coordinated and supervised the experiments and edited the manuscript.

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Correspondence to Robert A Hill or Akiko Nishiyama.

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Integrated supplementary information

Supplementary Figure 1 In vivo imaging and single-cell dynamics of division and disappearance.

(a) Diagram depicting transcranial in vivo imaging of NG2 cells (green) and NG2 cell-derived oligodendrocytes (yellow/red) in the upper layers of the cortex (top). Diagram depicting the expression of fluorescent proteins and oligodendrocyte lineage markers in NG2cre:ZEG:PLPDsRed transgenic mice (bottom). (b) Representative traces showing the behavior of single GFP-expressing NG2 cells in vivo over 10 days. Traces demonstrate single cells disappearing without division, dividing and disappearing, dividing without disappearing or remaining stable with a subpopulation differentiating into DsRed expressing oligodendrocytes. (c) Quantification from 82 cells from 3 mice show the percentages for each cellular behavior. Error bars, s.d.

Supplementary Figure 2 Age- and region-dependent oligodendrocyte maturation after NG2 cell division.

(a–b) Representative low and high magnification images captured from the cortex and corpus callosum of PLPDsRed mice given a single injection of EDU at P8 and sacrificed 4 or 10 days later. The majority of EDU+ cells are not DsRed+ (arrows) at P8+4 and P8+10. Occasional EDU+ cells express DsRed (arrowheads). (c) Quantification of the percentage of EDU+ cells that were also DsRed+ at 3 (P > 0.9999, t = 0.0), 4, (P = 0.2531, t = 2.197) 5 (P > 0.9999, t = 1.272), 6 (P = 0.0005, t = 4.646), 8 (P < 0.0001, t = 17.38) and 10 (P < 0.0001, t = 11.73) days after EDU injection at P8, showing the first appearance of double labeled cells at P8+4, and significantly higher values in the corpus callosum. (d–e) Representative low and high magnification images captured from the cortex and corpus callosum of PLPDsRed mice given a single injection of EDU at P21 and sacrificed 4 or 10 days later. Arrows: EDU+ DsRed- cells. Arrowheads: EDU+ DsRed+ cells. (f) Quantification of the percentage of EDU+ cells that were also DsRed+ in the cortex and corpus callosum at 3 (p > 0.9999, t = 0.0), 4, (P > 0.9999, t = 0.0) 5 (P > 0.9999, t = 0.0), 6 (P < 0.0001, t = 5.943), 8 (P < 0.0001, t = 10.64) and 10 (P < 0.0001, t = 18.65) days after EDU injection, showing the first appearance of double labeled cells at P21+6 in the corpus callosum and P21+8 in the cortex, and significantly higher values in the corpus callosum. Error bars, s.d. Scale bars in low magnification images, 50μm. Scale bars in high magnification images, 20μm. P values were obtained by two-way ANOVA, Bonferroni post-hoc test.

Supplementary Figure 3 Experimental procedure for time-lapse imaging in forebrain slice cultures.

(a) Diagram depicting the preparation of forebrain slice cultures. (b) Timeline used for LPC experiments in Figure 5.

Supplementary Figure 4 Differentiation of a GFP-expressing cell without division in slice culture.

(a) Montage of images showing a GFP+ (green) neocortical cell (arrow) becoming DsRed+ (red) over the 78-hour imaging period (hours indicated in top right corner of each panel). At the end of the imaging session slices were fixed and immunolabeled with CC1 (blue) antibody demonstrating that the GFP+DsRed+ cell is a CC1+ oligodendrocyte. Scale bar, 25 μm.

Supplementary Figure 5 Division orientation and outcome of cell divisions in slice culture.

(a) Diagram showing the analysis of division orientation relative to the tangent on the pial surface in slice cultures followed by analysis of fate outcome after division with post hoc immunostaining. (b) Quantification of divisions in horizontal or vertical planes in control and LPC-treated slice cultures. Combined data from both cortex and corpus callosum show no significant change with LPC treatment (horizontal P = 0.243, t = 1.222) (vertical P = 0.244, t = 1.222) P values were obtained by unpaired two- tailed Student’s t-test. (c) Fate outcome of cells that divided along a horizontal or vertical plane. Data acquired from 56 cell pairs, 7 control slices and 9 LPC slices from 3 mice.

Supplementary Figure 6 Experimental procedure and timelines used for whisker sensory deprivation experiments.

(a) Diagram depicting whisker deprivation and analysis in fixed tissue. (b) Experimental timeline for unilateral whisker sensory deprivation in Figure 6. (c) Experimental timeline for unilateral whisker sensory deprivation in Figure 7.

Supplementary Figure 7 Whisker clipping does not alter oligodendrocyte generation in the motor cortex.

(a) Diagram showing the experimental timeline for labeling of NG2 cells in NG2creER:YFP mice with unilateral whisker clipping and subsequent perfusion and analysis in the control motor cortex. (b) The density of CC1+ oligodendrocytes in the motor cortex of the spared and deprived hemispheres at 4 and 6 days after the start of whisker clipping (t = 0.442, t = 0.374). (c) The phenotype of YFP+ cells in the motor cortex showing no differences in the density of cells at P6+4 and P6+6, (t = 1.00, t = 1.63). (d) The density of YFP+ CC1+ oligodendrocytes at P6+4 and P6+6 in the motor cortex of spared and deprived hemispheres (t = 0.424, t = 1.549) (e) The density of CC1+EDU+ cells at 2 and 4 days after EDU injection in the motor cortex of spared and deprived hemispheres (t = 0.456, t = 0.119). (f) The proportion of YFP+EDU+ cells that had differentiated into CC1+ oligodendrocytes at 2 and 4 days after EdU injection in the motor cortex of spared and deprived hemispheres (t = 0.731, t = 0.018). Data from 12 sections from 3 mice for each graph, P values obtained from paired two-tailed Student’s t-test.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 1225 kb)

Supplementary Methods Checklist (PDF 679 kb)

z stack captured in vivo from a NG2cre:ZEG:PLPDsRed mouse

Representative Z stack captured in vivo with two-photon fluorescence microscopy from a P30 NG2cre:ZEG:PLPDsRed mouse with a 3-μm step size (cortical depth indicated in top right corner in micrometers). Scale bar = 50 μm. Movie displayed at 20 frames per second. (AVI 8908 kb)

In vivo imaging of NG2 cell division

Time-lapse sequence of the same GFP+ cells in a NG2cre:ZEG transgenic mouse with images captured once a day starting at P20 (age indicated in upper right corner) showing a single NG2 cell dividing multiple times over the imaging period (arrows). Scale bar = 20 μm. Movie displayed at 2 frames per second. Montage of images shown in Figure 3. (AVI 45 kb)

NG2 cell division and disappearance in vivo

Time-lapse sequence of the same cortical region captured in vivo starting at P21 (age indicated in upper right corner) from a NG2cre:ZEG mouse showing GFP+ NG2 cells dividing (arrows) and then disappearing or migrating out of the field of view. Scale bar = 20 μm. Movie displayed at 2 frames per second. Montage of images shown in Figure 3. (AVI 56 kb)

In vivo imaging of NG2 cell differentiation without division

Time-lapse sequence of the same cortical region captured in vivo starting at P21 (age indicated in upper right corner) from a NG2cre:ZEG:PLPDsRed mouse showing dividing GFP+ cells (red arrows) and GFP+ cells becoming DsRed+ oligodendrocytes (blue arrows). For in vivo imaging experiments we never observed a GFP+ cell dividing and then becoming DsRed+. Scale bar = 50 μm. Movie displayed at 2 frames per second. Montage of images shown in Figure 4. (AVI 119 kb)

Division of GFP-expressing cells without becoming DsRed+ in a slice culture

Time-lapse sequence showing GFP+ cells in a control ex vivo cortical slice culture from an NG2creZEG:PLPDsRed mouse showing dividing GFP+ cells (arrows) or differentiating GFP+ cells (becoming DsRed+) but no cells dividing and then becoming DsRed+. Scale bar = 20 μm. Movie displayed at 2 frames per second. Montage of images shown in Figure 5 with hour imaged indicated in each panel. (AVI 45 kb)

NG2 cell differentiation without cell division in ex vivo slice cultures

Time-lapse sequence showing GFP+ cells becoming DsRed+ without division (arrow) in a control ex vivo cortical slice culture from an NG2creZEG:PLPDsRed mouse. Scale bar = 20 μm. Movie displayed at 2 frames per second. Montage of images shown in Supplementary Fig. 3 with hour imaged indicated in each panel. (AVI 78 kb)

NG2 cell division and differentiation after LPC exposure in ex vivo slice cultures

Time-lapse sequence showing one of the GFP+ cells becoming DsRed+ after division (arrow) in an ex vivo cortical slice culture exposed to LPC from an NG2creZEG:PLPDsRed mouse. This was only observed in slices exposed to LPC but never in control slices. Scale bar = 20 μm. Movie displayed at 2 frames per second. Montage of images shown in Figure 5 with hour imaged indicated in each panel. (AVI 53 kb)

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Hill, R., Patel, K., Goncalves, C. et al. Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division. Nat Neurosci 17, 1518–1527 (2014). https://doi.org/10.1038/nn.3815

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