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Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling

Nature Cell Biology volume 15, pages 602–613 (2013)Cite this article

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Abstract

The adult mouse subependymal zone (SEZ) harbours adult neural stem cells (aNSCs) that give rise to neuronal and oligodendroglial progeny. However it is not known whether the same aNSC can give rise to neuronal and oligodendroglial progeny or whether these distinct progenies constitute entirely separate lineages. Continuous live imaging and single-cell tracking of aNSCs and their progeny isolated from the mouse SEZ revealed that aNSCs exclusively generate oligodendroglia or neurons, but never both within a single lineage. Moreover, activation of canonical Wnt signalling selectively stimulated proliferation within the oligodendrogliogenic lineage, resulting in a massive increase in oligodendrogliogenesis without changing lineage choice or proliferation within neurogenic clones. In vivo activation or inhibition of canonical Wnt signalling respectively increased or decreased the number of Olig2 and PDGFR- α positive cells, suggesting that this pathway contributes to the fine tuning of oligodendrogliogenesis in the adult SEZ.

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Figure 1: Oligodendroglial progenitors are enriched within the dorsal wall of the adult SEZ.
Figure 2: Neuro- and oligodendrogliogenic lineage trees tracked by live imaging in cultures of the dorsal plus lateral wall of the adult SEZ.
Figure 3: Canonical Wnt signalling augments oligodendrogliogenesis in culture.
Figure 4: Oligodendroglio- and neurogenic lineage trees tracked by live imaging following Wnt3a treatment.
Figure 5: Wnt3a treatment increases the proliferation of the oligodendroglial progenitors without inducing a switch in cell fate.
Figure 6: Local overexpression of Wnt3 enhances oligodendrogliogenesis whereas inhibition of canonical Wnt signalling decreases oligodendrogliogenesis in the adult SEZ.
Figure 7: Local Wnt3 overexpression increases oligondendrogliogenesis in the adult SEZ without altering the neuronal and astroglial population.
Figure 8: Local Wnt3 overexpression augments proliferation in the adult SEZ.

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References

  1. Ihrie, R. A. & Alvarez-Buylla, A. Lake-front property: A unique germinal niche by the lateral ventricles of the adult brain. Neuron 70, 674–686 (2011).

    Article  CAS  Google Scholar 

  2. Lois, C., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Chain migration of neuronal precursors. Science 271, 978–981 (1996).

    Article  CAS  Google Scholar 

  3. Gonzalez-Perez, O. & Alvarez-Buylla, A. Oligodendrogenesis in thesubventricular zone and the role of epidermal growth factor. Brain Res. Rev. 67, 147–156 (2011).

    Article  CAS  Google Scholar 

  4. 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 

  5. Hack, M. A. et al. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat. Neurosci. 8, 865–872 (2005).

    Article  CAS  Google Scholar 

  6. Picard-Riera, N. et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci. USA 99, 13211–13216 (2002).

    Article  CAS  Google Scholar 

  7. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    Article  CAS  Google Scholar 

  8. Mirzadeh, Z., Merkle, F. T., Soriano-Navarro, M., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265–278 (2008).

    Article  CAS  Google Scholar 

  9. Ihrie, R. A. et al. Persistent sonic hedgehog signalling in adult brain determines neural stem cell positional identity. Neuron 71, 250–262 (2011).

    Article  CAS  Google Scholar 

  10. Brill, M. S. et al. Adult generation of glutamatergic olfactory bulb interneurons. Nat. Neurosci. 12, 1524–1533 (2009).

    Article  CAS  Google Scholar 

  11. Merkle, F. T., Mirzadeh, Z. & Alvarez-Buylla, A. Mosaic organization of neural stem cells in the adult brain. Science 317, 381–384 (2007).

    Article  CAS  Google Scholar 

  12. Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Ann. Rev. Neurosci. 32, 149–184 (2009).

    Article  CAS  Google Scholar 

  13. Beckervordersandforth, R. et al. In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell 7, 744–758 (2010).

    Article  CAS  Google Scholar 

  14. Colak, D. et al. Adult neurogenesis requires Smad4-mediated bone morphogenic protein signalling in stem cells. J. Neurosci. 28, 434–446 (2008).

    Article  CAS  Google Scholar 

  15. Jablonska, B. et al. Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat. Neurosci. 13, 541–550 (2010).

    Article  CAS  Google Scholar 

  16. Costa, M. R. et al. Continuous live imaging of adult neural stem cell division and lineage progression in vitro. Development 138, 1057–1068 (2011).

    Article  CAS  Google Scholar 

  17. Ortega, F. et al. Using an adherent cell culture of the mouse subependymal zone to study the behaviour of adult neural stem cells on a single-cell level. Nat. Protoc. 6, 1847–1859 (2011).

    Article  CAS  Google Scholar 

  18. Doetsch, F. The glial identity of neural stem cells. Nat. Neurosci. 6, 1127–1134 (2003).

    Article  CAS  Google Scholar 

  19. Pastrana, E., Cheng, L. C. & Doetsch, F. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc. Natl Acad. Sci. USA 106, 6387–6392 (2009).

    Article  CAS  Google Scholar 

  20. Marinaro, C. et al. Wnt signalling has opposing roles in the developing and the adult brain that are modulated by Hipk1. Cereb. Cortex 10, 2415–2427 (2012).

    Article  Google Scholar 

  21. 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 

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

    CAS  PubMed  Google Scholar 

  23. Simon, C., Lickert, H., Götz, M. & Dimou, L. Sox10-iCreER(T2): A mouse line to inducibly trace the neural crest and oligodendrocyte lineage. Genesis 6, 506–515 (2012).

    Article  Google Scholar 

  24. Nakamura, T., Colbert, M. C. & Robbins, J. Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system. Circ. Res. 98, 1547–1554 (2006).

    Article  CAS  Google Scholar 

  25. Hirrlinger, P. G. et al. Expression of reef coral fluorescent proteins in the central nervous system of transgenic mice. Mol. Cell Neurosci. 30, 291–303 (2005).

    Article  CAS  Google Scholar 

  26. Mori, T. et al. Inducible gene deletion in astroglia and radial glia–a valuable tool for functional and lineage analysis. Glia 54, 21–34 (2006).

    Article  Google Scholar 

  27. Michaelidis, T. M. & Lie, D. C. Wnt signalling and neural stem cells: Caught in the Wnt web. Cell Tissue Res. 331, 193–210 (2008).

    Article  Google Scholar 

  28. Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).

    Article  CAS  Google Scholar 

  29. Matsumoto, Y. et al. Differential proliferation rhythm of neural progenitor and oligodendrocyte precursor cells in the young adult hippocampus. PLoS One 6, e27628 (2011).

    Article  CAS  Google Scholar 

  30. Semenov, M. V. et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11, 951–961 (2001).

    Article  CAS  Google Scholar 

  31. Lie, D. C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).

    Article  CAS  Google Scholar 

  32. Fuerer, C. & Nusse, R. Lentiviral vectors to probe and manipulate the Wnt signalling pathway. PLoS One 5, e9370 (2010).

    Article  Google Scholar 

  33. Fischer, J. et al. Prospective isolation of adult neural stem cells from the mouse subependymal zone. Nat. Protoc. 6, 1981–1989 (2011).

    Article  CAS  Google Scholar 

  34. Gonzalez-Perez, O., Romero-Rodriguez, R., Soriano-Navarro, M., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Epidermal growth factor induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells 27, 2032–2043 (2009).

    Article  CAS  Google Scholar 

  35. Dimou, L., Simon, C., Kirchhoff, F., Takebayashi, H. & Götz, M. Progeny of Olig2-expressing progenitors in the grey and white matter of the adult mouse cerebral cortex. J. Neurosci. 28, 10434–10442 (2008).

    Article  CAS  Google Scholar 

  36. Lois, C. & Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148 (1994).

    Article  CAS  Google Scholar 

  37. Saghatelyan, A. Role of blood vessels in the neuronal migration. Semin. Cell Dev. Biol. 20, 744–750 (2009).

    Article  CAS  Google Scholar 

  38. Snapyan, M. et al. Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signalling. J. Neurosci. 29, 4172–4188 (2009).

    Article  CAS  Google Scholar 

  39. Li, H., de Faria, J. P., Andrew, P., Nitarska, J. & Richardson, W. D. Phosphorylation regulates OLIG2 cofactor choice and the motor neuron-oligodendrocyte fate switch. Neuron 69, 918–929 (2011).

    Article  CAS  Google Scholar 

  40. Chojnacki, A. & Weiss, S. Production of neurons, astrocytes and oligodendrocytes from mammalian CNS stem cells. Nat. Protoc. 3, 935–940 (2008).

    Article  CAS  Google Scholar 

  41. Gabay, L., Lowell, S., Rubin, L. L. & Anderson, D. J. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40, 485–499 (2003).

    Article  CAS  Google Scholar 

  42. Aguirre, A. & Gallo, V. Reduced EGFR signalling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination. Neuron Glia Biol. 3, 209–220 (2007).

    Article  Google Scholar 

  43. Hevner, R. F., Hodge, R. D., Daza, R. A. & Englund, C. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci. Res. 55, 223–233 (2006).

    Article  CAS  Google Scholar 

  44. Chew, L. J. et al. SRY-box containing gene 17 regulates the Wnt/ β-catenin signalling pathway in oligodendrocyte progenitor cells. J. Neurosci. 31, 13921–13935 (2011).

    Article  CAS  Google Scholar 

  45. Langseth, A. J. et al. Wnts influence the timing and efficiency of oligodendrocyte precursor cell generation in the telencephalon. J. Neurosci. 30, 13367–13372 (2010).

    Article  CAS  Google Scholar 

  46. Feigenson, K., Reid, M., See, J., Crenshaw, E. B. 3rd & Grinspan, J. B. Wnt signalling is sufficient to perturb oligodendrocyte maturation. Mol. Cell Neurosci. 42, 255–265 (2009).

    Article  CAS  Google Scholar 

  47. White, B. D. et al. β-catenin signalling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells 28, 297–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Simon, C., Götz, M. & Dimou, L. Progenitors in the adult cerebral cortex: cell cycle properties and regulation by physiological stimuli and injury. Glia 59, 869–881 (2011).

    Article  Google Scholar 

  49. Costa, M. R., Wen, G., Lepier, A., Schroeder, T. & Götz, M. Par-complex proteins promote proliferative progenitor divisions in the developing mouse cerebral cortex. Development 135, 11–22 (2008).

    Article  CAS  Google Scholar 

  50. Eilken, H. M., Nishikawa, S. & Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009).

    Article  CAS  Google Scholar 

  51. Schroeder, T. Long-term single-cell imaging of mammalian stem cells. Nat. Methods 8, S30–S35 (2011).

    Article  CAS  Google Scholar 

  52. Rieger, M. A., Hoppe, P. S., Smejkal, B. M., Eitelhuber, A. C. & Schroeder, T. Hematopoietic cytokines can instruct lineage choice. Science 325, 217–218 (2009).

    Article  CAS  Google Scholar 

  53. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001).

    Article  CAS  Google Scholar 

  54. Heinrich, C. et al. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol. 8, e1000373 (2010).

    Article  Google Scholar 

  55. Brill, M. S. et al. A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb. J. Neurosci. 28, 6439–6452 (2008).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to M. Götz (LMU Munich) for discussion and valuable comments on the manuscript. We also thank T. Simon-Ebert and G. Jaeger for excellent technical assistance. We are indebted to the Graduate School of Systemic Neuroscience for financial support of the time-lapse video microscope. This work was supported by grants of the Bundesministerium für Bildung und Forschung (01GN 1009A), the Bavarian State Ministry of Sciences, Research and the Arts (ForNeuroCell), and the Belgian Science Policy Office (P7/20 Wibrain) to B.B. and the Deutsche Forschungsgemeinschaft to B.B. (BE 4182/2-2) and T.S. (SCHR 1142/1-2).

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  1. Sergio Gascón and Giacomo Masserdotti: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Schillerstrasse 46, D-80336 Munich, Germany

    Felipe Ortega, Sergio Gascón, Giacomo Masserdotti, Aditi Deshpande, Christiane Simon, Leda Dimou & Benedikt Berninger

  2. Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, D-55128 Mainz, Germany

    Felipe Ortega & Benedikt Berninger

  3. Institute of Stem Cell Research, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany

    Sergio Gascón, Giacomo Masserdotti, Judith Fischer, Leda Dimou & Benedikt Berninger

  4. Institute of Biochemistry, Emil Fischer Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany

    D. Chichung Lie

  5. Stem Cell Dynamics Research Unit, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany

    Timm Schroeder

  6. Focus Program Translational Neuroscience, Johannes Gutenberg University, 55131 Mainz, Germany

    Benedikt Berninger

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Contributions

Experiments were designed by F.O. and B.B. F.O. carried out most of the experiments, analysed the data and prepared the figures. S.G. demonstrated Wnt3 secretion from overexpressing cells. G.M. carried out and analysed RT–PCR experiments. A.D., C.S. and L.D. helped with the in vivo experiments. J.F. carried out the FACS analysis. D.C.L. contributed the Wnt3 lentivirus. T.S. helped with the time-lapse experiments and contributed the analysis software. F.O and B.B. wrote the manuscript.

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Correspondence to Felipe Ortega or Benedikt Berninger.

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Supplementary Table 2

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Oligodendrogliogenic lineage progression in control cultures.

The video shows the same examples as depicted in Fig. 2b,c. Clonal founder cells exhibited the hallmarks of the aNSCs such as marked cell growth before division and slow cell cycle. Of note, in contrast to neurogenic clones, which typically remain compact through transit-amplifying divisions until reaching the neuroblast stage, oligodendrogliogenic clones show marked migratory behaviour at all stages. (AVI 5208 kb)

Oligodendrogliogenic lineage progression following Wnt3a treatment.

The video shows the example depicted in Fig. 4a,b. The culture was prepared from the adult SEZ of a hGFAP–RFP mouse. Note the upregulation of RFP in the clonal founder cell before division and the massive expansion of the clone in the presence of Wnt3a. (AVI 5860 kb)

The enhancement of oligodendrogliogenesis in adult SEZ culture is not due to a switch in cell fate.

The video shows the two clones depicted in Fig. 5a. Following a control period of approximately 7 days, recombinant Wnt3a was added to the culture medium addition of Wnt3a. No change was observed in the neurogenic clone (blue arrow) on Wnt3a treatment, whereas the length of the cell cycle was shortened in an asymmetrically dividing oligodendrogliogenic clone (red arrow). Note that the astroglial progeny did not respond to Wnt3a stimulation. (AVI 10028 kb)

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Ortega, F., Gascón, S., Masserdotti, G. et al. Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling. Nat Cell Biol 15, 602–613 (2013). https://doi.org/10.1038/ncb2736

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