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Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination

Nature Neuroscience volume 13, pages 541–550 (2010)Cite this article

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Abstract

The mechanisms that regulate the developmental potential of adult neural progenitor populations under physiological and pathological conditions remain poorly defined. Glutamic acid decarboxylase 65 (GAD65)- and Doublecortin (Dcx)-expressing cells constitute major progenitor populations in the adult mouse subventricular zone (SVZ). Under normal physiological conditions, SVZ-derived GAD65-positive and Dcx-positive cells expressed the transcription factor Pax6 and migrated along the rostral migratory stream to the olfactory bulb to generate interneurons. After lysolecithin-induced demyelination of corpus callosum, however, these cells altered their molecular and cellular properties and migratory path. Demyelination upregulated chordin in the SVZ, which redirected GAD65-positive and Dcx-positive progenitors from neuronal to glial fates, generating new oligodendrocytes in the corpus callosum. Our findings suggest that the lineage plasticity of SVZ progenitor cells could be a potential therapeutic strategy for diseased or injured brain.

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Figure 1: Demyelination increases GAD65-GFP–positive cells expressing glial lineage markers in the SVZ and corpus callosum.
Figure 2: Demyelination alters the migratory pathway and phenotype of GAD65-GFP–positive cells.
Figure 3: Cellular characterization of the corpus callosum in Dcx-GFP mice after demyelination.
Figure 4: Cell lineage plasticity of Dcx-expressing progenitors after demyelination.
Figure 5: GAD65-GFP–positive cells from the SVZ of LPC-injected brains generate Olig2- and GalC-positive cells in culture.
Figure 6: Chordin induces cell lineage plasticity in cultured SVZ GAD65-GFP–positive cells.
Figure 7: Chordin induces cell lineage plasticity in cultured SVZ Dcx-GFP–positive cells.
Figure 8: Chordin induces oligodendrogenesis in corpus callosum of GAD65-GFP and Dcx-GFP mice after demyelination.

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References

  1. Doetsch, F., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Regeneration of a germinal layer in the adult mammalian brain. Proc. Natl. Acad. Sci. USA 96, 11619–11624 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Palmer, T.D., Markakis, E.A., Willhoite, A.R., Safar, F. & Gage, F.H. Fibroblast growth factor 2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Palmer, T.D., Willhoite, A.R. & Gage, F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Shen, Q., Zhong, W., Jan, Y.N. & Temple, S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129, 4843–4853 (2002).

    CAS  PubMed  Google Scholar 

  6. Alvarez-Buylla, A. & Garcia-Verdugo, J.M. Neurogenesis in adult subventricular zone. J. Neurosci. 22, 629–634 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alvarez-Buylla, A. & Lim, D.A. For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Coskun, V. & Luskin, M.B. Intrinsic and extrinsic regulation of the proliferation and differentiation of cells in the rodent rostral migratory stream. J. Neurosci. Res. 69, 795–802 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Kim, Y., Comte, I., Szabo, G., Hockberger, P. & Szele, F.G. Adult mouse subventricular zone stem and progenitor cells are sessile and epidermal growth factor receptor negatively regulates neuroblast migration. PLoS One 4, e8122 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Ligon, K.L. et al. Development of NG2 neural progenitor cells requires Olig gene function. Proc. Natl. Acad. Sci. USA 103, 7853–7858 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aguirre, A., Dupree, J., Mangin, J.M. & Gallo, V. A functional role for EGFR signaling in myelination and remyelination. Nat. Neurosci. 10, 990–1002 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Nait-Oumesmar, B., Picard-Riéra, N., Kerninon, C. & Baron-Van Evercooren, A . The role of SVZ-derived neural precursors in demyelinating diseases: From animal models to multiple sclerosis. J. Neurol. Sci. 265, 26–31 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Baumann, N. & Pham-Dinh, D. Biology of oligodendrocytes and myelin in the mammalian central nervous system. Physiol. Rev. 81, 871–927 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Levine, J.M., Reynolds, R. & Fawcett, J.W. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 24, 39–47 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Jessberger, S., Toni, N., Clemenson, G.D. Jr., Ray, J. & Gage, F.H. Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat. Neurosci. 11, 888–893 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buffo, A. et al. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc. Natl. Acad. Sci. USA 102, 18183–18188 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walker, T.L., Yasuda, T., Adams, D.J. & Bartlett, P.F. The doublecortin-expressing population in the developing and adult brain contains multipotential precursors in addition to neuronal-lineage cells. J. Neurosci. 27, 3734–3742 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ligon, K.L., Fancy, S.P., Franklin, R.J. & Rowitch, D.H. Olig gene function in CNS development and disease. Glia 54, 1–10 (2006).

    Article  PubMed  Google Scholar 

  22. Canoll, P. & Goldman, J. The interface between glial progenitors and gliomas. Acta Neuropathol. 116, 465–477 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Franklin, R.J. & Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Staugaitis, S.M. & Trapp, B.D. NG2-positive glia in the human central nervous system. Neuron Glia Biol. 5, 35–44 (2009).

    Article  PubMed  Google Scholar 

  25. Heins, N. et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nat. Neurosci. 5, 308–315 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Jablonska, B. et al. Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone. J. Cell Biol. 179, 1231–1245 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Goings, G.E., Sahni, V. & Szele, F.G. Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury. Brain Res. 996, 213–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, H.L. & Panchision, D.M. Concise review: bone morphogenetic protein pleiotropism in neural stem cells and their derivatives–alternative pathways, convergent signals. Stem Cells 25, 63–68 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. See, J.M.P. & Grinspan, J.B.P. Sending mixed signals: bone morphogenetic protein in myelination and demyelination. J. Neuropathol. Exp. Neurol. 68, 595–604 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Mehler, M.F., Mabie, P.C., Zhu, G., Gokhan, S. & Kessler, J.A. Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate. Dev. Neurosci. 22, 74–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Mekki-Dauriac, S., Agius, E., Kan, P. & Cochard, P. Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development 129, 5117–5130 (2002).

    CAS  PubMed  Google Scholar 

  33. Gomes, W.A., Mehler, M.F. & Kessler, J.A. Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev. Biol. 255, 164–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Samanta, J. et al. BMPR1a Signaling determines numbers of oligodendrocytes and Calbindin-expressing interneurons in the cortex. J. Neurosci. 27, 7397–7407 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. See, J. et al. BMP signaling mutant mice exhibit glial cell maturation defects. Mol. Cell. Neurosci. 35, 171–182 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, Y. et al. Bone morphogenetic protein–6 reduces ischemia-induced brain damage in rats. Stroke 32, 2170–2178 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Kondo, T. Common mechanism underlying oligodendrocyte development and oligodendrogliomagenesis. Brain Nerve 61, 741–751 (2009).

    CAS  PubMed  Google Scholar 

  38. Hampton, D.W. et al. A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo. Eur. J. Neurosci. 26, 3024–3035 (2007).

    Article  PubMed  Google Scholar 

  39. Chou, J. et al. Neuroregenerative effects of BMP7 after stroke in rats. J. Neurol. Sci. 240, 21–29 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Shen, H., Luo, Y., Kuo, C.-C. & Wang, Y. BMP7 reduces synergistic injury induced by methamphetamine and ischemia in mouse brain. Neurosci. Lett. 442, 15–18 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Israelsson, C. et al. Genetically modified bone morphogenetic protein signaling alters traumatic brain injury-induced gene expression responses in the adult mouse. J. Neurosci. Res. 84, 47–57 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Bani-Yaghoub, M. et al. Neuroregenerative strategies in the brain: emerging significance of bone morphogenetic protein 7 (BMP7). Biochem. Cell Biol. 86, 361–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Zhao, C., Fancy, S.P.J., Kotter, M.R., Li, W.-W. & Franklin, R.J.M. Mechanisms of CNS remyelination—the key to therapeutic advances. J. Neurol. Sci. 233, 87–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Fuller, M.L. et al. Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann. Neurol. 62, 288–300 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Ara, J. et al. Bone morphogenetic proteins 4, 6 and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitis. J. Neurosci. Res. 86, 125–135 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chang, A. et al. Neurogenesis in the chronic lesions of multiple sclerosis. Brain 131, 2366–2375 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Deininger, M., Meyermann, R. & Schluesener, H. Detection of two transforming growth factor-beta-related morphogens, bone morphogenetic proteins-4 and -5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions. Acta Neuropathol. 90, 76–79 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. 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  PubMed  PubMed Central  Google Scholar 

  50. Aguirre, A., Rizvi, T.A., Ratner, N. & Gallo, V. Overexpression of the epidermal growth factor receptor confers migratory properties to nonmigratory postnatal neural progenitors. J. Neurosci. 25, 11092–11106 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank F. Gage (Salk Institute) and J. Goldman (Columbia University) for the gift of pNIT-GFP and dS-Red retrovirus and D. Rowitch (University of California San Francisco) for the gift of antibodies to Olig2. We thank T. Hawley for assistance with FACS sorting. We are particularly grateful to J. Corbin for discussion. This work was supported by US National Institutes of Health grants R01NS045702 and R01NS056427 to V.G., K99NS057944 to A.A., R01NS047344 and R01AG024984 to H.S. and R01NS048271 to G.M. and by the Hungarian National Office for Research and Technology GVOP-3.1.1.-2004-05-0230-/3.0 to G.S. and US National Institutes of Health Intellectual and Developmental Disabilities Research Center P30HD40677 to V.G.

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  1. Beata Jablonska and Adan Aguirre: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA

    Beata Jablonska, Adan Aguirre, Matthew Raymond & Vittorio Gallo

  2. George Washington University, Institute for Biomedical Sciences, Washington, DC, USA

    Matthew Raymond

  3. Department of Gene Technology and Developmental Neurobiology, Institute of Experimental Medicine, Budapest, Hungary

    Gabor Szabo

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Yasuji Kitabatake, Kurt A Sailor, Guo-Li Ming & Hongjun Song

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Contributions

B.J. and A.A. designed, performed and analyzed all of the experiments. M.R. performed some of the in vivo experiments, cell imaging and cell counting. G.S. generated and provided the GAD65-GFP mice. Y.K., K.A.S., G.M. and H.S. generated and provided the Dcx-CreERT2 mice. V.G. designed the experiments with B.J. and A.A., supervised the project and wrote the manuscript with input from B.J.

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Correspondence to Vittorio Gallo.

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Jablonska, B., Aguirre, A., Raymond, M. et al. Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci 13, 541–550 (2010). https://doi.org/10.1038/nn.2536

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