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PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice

Abstract

Platelet-derived growth factor α receptor (PDGFRA)/NG2–expressing glia are distributed throughout the adult CNS. They are descended from oligodendrocyte precursors (OLPs) in the perinatal CNS, but it is not clear whether they continue to generate myelinating oligodendrocytes or other differentiated cells during normal adult life. We followed the fates of adult OLPs in Pdgfra-creERT2/Rosa26-YFP double-transgenic mice and found that they generated many myelinating oligodendrocytes during adulthood; >20% of all oligodendrocytes in the adult mouse corpus callosum were generated after 7 weeks of age, raising questions about the function of the late-myelinating axons. OLPs also produced some myelinating cells in the cortex, but the majority of adult-born cortical cells did not appear to myelinate. We found no evidence for astrocyte production in gray or white matter. However, small numbers of projection neurons were generated in the forebrain, especially in the piriform cortex, which is the main target of the olfactory bulb.

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Figure 1: Antigenic properties of adult OLPs/NG2 cells.
Figure 2: Cumulative BrdU labeling of adult OLPs/NG2 cells in vivo.
Figure 3: PDGFRA+ adult OLPs generate differentiated oligodendrocyte lineage cells.
Figure 4: Evidence for myelin protein synthesis in adult-born oligodendrocytes.
Figure 5: Adult OLPs generate myelinating oligodendrocytes.
Figure 6: Adult OLPs do not generate astrocytes.
Figure 7: OLPs generate cortical projection neurons in vivo.
Figure 8: Morphologies of YFP-labeled neurons in the piriform cortex.

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References

  1. Hall, A., Giese, N.A. & Richardson, W.D. Spinal cord oligodendrocytes develop from ventrally derived progenitor cells that express PDGF alpha-receptors. Development 122, 4085–4094 (1996).

    CAS  PubMed  Google Scholar 

  2. Butt, A.M. et al. PDGF-alpha receptor and myelin basic protein mRNAs are not coexpressed by oligodendrocytes in vivo: a double in situ hybridization study in the anterior medullary velum of the neonatal rat. Mol. Cell. Neurosci. 8, 311–322 (1997).

    Article  CAS  Google Scholar 

  3. Nishiyama, A., Chang, A. & Trapp, B.D. NG2+ glial cells: a novel glial cell population in the adult brain. J. Neuropathol. Exp. Neurol. 58, 1113–1124 (1999).

    Article  CAS  Google Scholar 

  4. Ffrench-Constant, C. & Raff, M.C. Proliferating bipotential glial progenitor cells in adult rat optic nerve. Nature 319, 499–502 (1986).

    Article  CAS  Google Scholar 

  5. Wolswijk, G. & Noble, M. Identification of an adult-specific glial progenitor cell. Development 105, 387–400 (1989).

    CAS  PubMed  Google Scholar 

  6. Pringle, N.P., Mudhar, H.S., Collarini, E.J. & Richardson, W.D. PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 115, 535–551 (1992).

    CAS  PubMed  Google Scholar 

  7. Shi, J., Marinovich, A. & Barres, B.A. Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J. Neurosci. 18, 4627–4636 (1998).

    Article  CAS  Google Scholar 

  8. Butt, A.M., Kiff, J., Hubbard, P. & Berry, M. Synantocytes: new functions for novel NG2 expressing glia. J. Neurocytol. 31, 551–565 (2002).

    Article  CAS  Google Scholar 

  9. Dawson, M.R., Polito, A., Levine, J.M. & Reynolds, R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol. Cell. Neurosci. 24, 476–488 (2003).

    Article  CAS  Google Scholar 

  10. Polito, A. & Reynolds, R. NG2-expressing cells as oligodendrocyte progenitors in the normal and demyelinated adult central nervous system. J. Anat. 207, 707–716 (2005).

    Article  Google Scholar 

  11. Ong, W.Y. & Levine, J.M. A light and electron microscopic study of NG2 chondroitin sulfate proteoglycan–positive oligodendrocyte precursor cells in the normal and kainate-lesioned rat hippocampus. Neuroscience 92, 83–95 (1999).

    Article  CAS  Google Scholar 

  12. Bergles, D.E., Roberts, J.D., Somogyi, P. & Jahr, C.E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).

    Article  CAS  Google Scholar 

  13. Butt, A.M. et al. Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter. Glia 26, 84–91 (1999).

    Article  CAS  Google Scholar 

  14. Lin, S.C. et al. Climbing fiber innervation of NG2-expressing glia in the mammalian cerebellum. Neuron 46, 773–785 (2005).

    Article  CAS  Google Scholar 

  15. Raff, M.C., Miller, R.H. & Noble, M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303, 390–396 (1983).

    Article  CAS  Google Scholar 

  16. Kondo, T. & Raff, M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754–1757 (2000).

    Article  CAS  Google Scholar 

  17. Nishiyama, A., Watanabe, M., Yang, Z. & Bu, J. Identity, distribution and development of polydendrocytes: NG2-expressing glial cells. J. Neurocytol. 31, 437–455 (2002).

    Article  CAS  Google Scholar 

  18. van Heyningen, P., Calver, A.R. & Richardson, W.D. Control of progenitor cell number by mitogen supply and demand. Curr. Biol. 11, 232–241 (2001).

    Article  CAS  Google Scholar 

  19. Nowakowski, R.S., Lewin, S. & Miller, M. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J. Neurocytol. 18, 311–318 (1989).

    Article  CAS  Google Scholar 

  20. Butt, A.M. & Ransom, B.R. Visualization of oligodendrocytes and astrocytes in the intact rat optic nerve by intracellular injection of lucifer yellow and horseradish peroxidase. Glia 2, 470–475 (1989).

    Article  CAS  Google Scholar 

  21. Hachem, S. et al. Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia 51, 81–97 (2005).

    Article  CAS  Google Scholar 

  22. Jackson, E.L. et al. PDGFR alpha–positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51, 187–199 (2006).

    Article  CAS  Google Scholar 

  23. Gensert, J.M. & Goldman, J.E. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19, 197–203 (1997).

    Article  CAS  Google Scholar 

  24. Watanabe, M., Toyama, Y. & Nishiyama, A. Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion. J. Neurosci. Res. 69, 826–836 (2002).

    Article  CAS  Google Scholar 

  25. Sturrock, R.R. Myelination of the mouse corpus callosum. Neuropathol. Appl. Neurobiol. 6, 415–420 (1980).

    Article  CAS  Google Scholar 

  26. McCarthy, G.F. & Leblond, C.P. Radioautographic evidence for slow astrocyte turnover and modest oligodendrocyte production in the corpus callosum of adult mice infused with 3H-thymidine. J. Comp. Neurol. 271, 589–603 (1988).

    Article  CAS  Google Scholar 

  27. Fields, R.D. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 31, 361–370 (2008).

    Article  CAS  Google Scholar 

  28. Kukley, M., Capetillo-Zarate, E. & Dietrich, D. Vesicular glutamate release from axons in white matter. Nat. Neurosci. 10, 311–320 (2007).

    Article  CAS  Google Scholar 

  29. Ziskin, J.L., Nishiyama, A., Rubio, M., Fukaya, M. & Bergles, D.E. Vesicular release of glutamate from unmyelinated axons in white matter. Nat. Neurosci. 10, 321–330 (2007).

    Article  CAS  Google Scholar 

  30. Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006).

    Article  CAS  Google Scholar 

  31. Nait-Oumesmar, B. et al. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur. J. Neurosci. 11, 4357–4366 (1999).

    Article  CAS  Google Scholar 

  32. Zhu, X., Bergles, D.E. & Nishiyama, A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135, 145–157 (2008).

    Article  CAS  Google Scholar 

  33. Keirstead, H.S., Levine, J.M. & Blakemore, W.F. Response of the oligodendrocyte progenitor cell population (defined by NG2 labeling) to demyelination of the adult spinal cord. Glia 22, 161–170 (1998).

    Article  CAS  Google Scholar 

  34. Tamura, Y. et al. Multi-directional differentiation of doublecortin- and NG2-immunopositive progenitor cells in the adult rat neocortex in vivo. Eur. J. Neurosci. 25, 3489–3498 (2007).

    Article  Google Scholar 

  35. Karadottir, R., Hamilton, N.B., Bakiri, Y. & Attwell, D. Spiking and nonspiking classes of oligodendrocyte precursor cell in CNS white matter. Nat. Neurosci. 11, 450–456 (2008).

    Article  CAS  Google Scholar 

  36. Suzuki, N. & Bekkers, J.M. Neural coding by two classes of principal cells in the mouse piriform cortex. J. Neurosci. 26, 11938–11947 (2006).

    Article  CAS  Google Scholar 

  37. Aguirre, A.A., Chittajallu, R., Belachew, S. & Gallo, V. NG2-expressing cells in the subventricular zone are type C-like cells and contribute to interneuron generation in the postnatal hippocampus. J. Cell Biol. 165, 575–589 (2004).

    Article  CAS  Google Scholar 

  38. Dayer, A.G., Cleaver, K.M., Abouantoun, T. & Cameron, H.A. New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J. Cell Biol. 168, 415–427 (2005).

    Article  CAS  Google Scholar 

  39. Kokoeva, M.V., Yin, H. & Flier, J.S. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679–683 (2005).

    Article  CAS  Google Scholar 

  40. Shapiro, L.A. et al. Origin, migration and fate of newly generated neurons in the adult rodent piriform cortex. Brain Struct. Funct. 212, 133–148 (2007).

    Article  Google Scholar 

  41. Gould, E., Reeves, A.J., Graziano, M.S. & Gross, C.G. Neurogenesis in the neocortex of adult primates. Science 286, 548–552 (1999).

    Article  CAS  Google Scholar 

  42. Zhao, M. et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc. Natl. Acad. Sci. USA 100, 7925–7930 (2003).

    Article  CAS  Google Scholar 

  43. Rakic, P. Adult neurogenesis in mammals: an identity crisis. J. Neurosci. 22, 614–618 (2002).

    Article  Google Scholar 

  44. Houweling, A.R. & Brecht, M. Behavioural report of single neuron stimulation in somatosensory cortex. Nature 451, 65–68 (2008).

    Article  CAS  Google Scholar 

  45. Huber, D. et al. Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice. Nature 451, 61–64 (2008).

    Article  CAS  Google Scholar 

  46. Magavi, S.S., Leavitt, B.R. & Macklis, J.D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

    Article  CAS  Google Scholar 

  47. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  Google Scholar 

  48. Fogarty, M. et al. Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex. J. Neurosci. 27, 10935–10946 (2007).

    Article  CAS  Google Scholar 

  49. Young, K.M., Fogarty, M., Kessaris, N. & Richardson, W.D. Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb. J. Neurosci. 27, 8286–8296 (2007).

    Article  CAS  Google Scholar 

  50. Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, New York, 2001).

    Google Scholar 

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Acknowledgements

We thank our colleagues in the Wolfson Institute for Biomedical Research for discussions, help and encouragement. Special thanks to M. Grist and U. Dennehy for expert technical assistance and to T. Mitsumori for helping to construct the Fgfr3-icreERT2 transgene. Thanks also to D. Attwell for critically reading the manuscript and L. Dimou and M. Götz for exchanging data before publication. L.E.R. was supported by a collaborative studentship from the Biotechnology and Biological Sciences Research Council and Eisai London Research Laboratories at University College London. F.J. held a Marie Curie Fellowship from the European Union. K.M.Y. is an Alzheimer's Society Fellow in Stem Cell Research. M.R. and A.W. hold studentships from The Wellcome Trust and K.P. has a studentship from the Medical Research Council. We are grateful to the Gatsby Foundation for the purchase of a two-photon microscope and to M. Häusser for providing access to it. This work was also supported by Programme grants from the Medical Research Council and The Wellcome Trust.

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Contributions

F.J. made the Pdgfra-creERT2 mice and performed preliminary characterization. L.E.R. analyzed the mice, made the initial observations of adult oligodendrogenesis and neurogenesis, and contributed quantification for Figures 1,2,3, 7 and Supplementary Figure 2. K.M.Y. extended the observations, carried out all of the confocal microscopy and in situ hybridization and contributed substantially to all of the experiments. A.W. quantified olfactory bulb neurogenesis. K.P. contributed to the BrdU cumulative label experiments and quantified neurogenesis. M.R. performed the cell-filling experiments and two-photon microscopy. K.M.Y., N.K. and W.D.R. devised and supervised the experiments. W.D.R. obtained funding and wrote the paper.

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Correspondence to William D Richardson.

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Rivers, L., Young, K., Rizzi, M. et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11, 1392–1401 (2008). https://doi.org/10.1038/nn.2220

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