Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression

Nature Neuroscience volume 12, pages 418–427 (2009)Cite this article

Abstract

In neurons, serum response factor (SRF)-directed transcription regulates migration, axon pathfinding and synapse function. We found that forebrain-specific, neuron-restricted SRF ablation in mice elevated oligodendrocyte precursors while inhibiting terminal oligodendrocyte differentiation. Myelin gene and protein expression were downregulated and we observed a lack of oligodendrocytes in mixed neuron/glia and oligodendrocyte-enriched cultures derived from Srf−/− mutants. Ultrastructural inspection revealed myelination defects and axonal degeneration in Srf−/− mutants. Consistent with our finding that neuronal SRF depletion impaired oligodendrocyte fate in a non–cell autonomous manner, neuron-restricted expression of constitutively active SRF-VP16 affected neighboring oligodendrocyte maturation. Genome-wide transcriptomics identified candidate genes for paracrine regulation of oligodendrocyte development, including connective tissue growth factor (CTGF), whose expression is repressed by SRF. Adenovirus-mediated CTGF expression in vivo revealed that CTGF blocks excessive oligodendrocyte differentiation. In vitro, CTGF-mediated inhibition of oligodendrocyte maturation involved sequestration and thereby counteraction of insulin growth factor 1–stimulated oligodendrocyte differentiation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genome-wide profiling of SRF target genes in the brain.
Figure 2: SRF depletion affects oligodendrocyte differentiation in vivo.
Figure 3: Electron-microscopic analysis of hypomyelination in the Srf mutant corpus callosum.
Figure 4: Absence of oligodendrocytes in Srf mutant oligodendrocyte-enriched cultures.
Figure 5: Loss of neuronal SRF affects oligodendrocyte number in mixed neuron/glia cultures.
Figure 6: SRF represses CTGF in vivo and in vitro.
Figure 7: CTGF expression in vivo impairs oligodendrocyte development.
Figure 8: CTGF inhibits oligodendrocyte differentiation in vitro by counteracting IGF1.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Durand, B. & Raff, M. A cell-intrinsic timer that operates during oligodendrocyte development. Bioessays 22, 64–71 (2000).

    Article  CAS  Google Scholar 

  3. Bozzali, M. & Wrabetz, L. Axonal signals and oligodendrocyte differentiation. Neurochem. Res. 29, 979–988 (2004).

    Article  CAS  Google Scholar 

  4. Chesik, D., De Keyser, J. & Wilczak, N. Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS. J. Mol. Neurosci. 35, 81–90 (2008).

    Article  CAS  Google Scholar 

  5. Simons, M. & Trajkovic, K. Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis. J. Cell Sci. 119, 4381–4389 (2006).

    Article  CAS  Google Scholar 

  6. Nicolay, D.J., Doucette, J.R. & Nazarali, A.J. Transcriptional control of oligodendrogenesis. Glia 55, 1287–1299 (2007).

    Article  Google Scholar 

  7. Wegner, M. A matter of identity: transcriptional control in oligodendrocytes. J. Mol. Neurosci. 35, 3–12 (2008).

    Article  CAS  Google Scholar 

  8. Posern, G. & Treisman, R. Actin' together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol. 16, 588–596 (2006).

    Article  CAS  Google Scholar 

  9. Ernst, W.H., Janknecht, R., Cahill, M.A. & Nordheim, A. Transcriptional repression mediated by the serum response factor. FEBS Lett. 357, 45–49 (1995).

    Article  CAS  Google Scholar 

  10. Rivera, V.M., Sheng, M. & Greenberg, M.E. The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. Genes Dev. 4, 255–268 (1990).

    Article  CAS  Google Scholar 

  11. Shaw, P.E., Frasch, S. & Nordheim, A. Repression of c-fos transcription is mediated through p67SRF bound to the SRE. EMBO J. 8, 2567–2574 (1989).

    Article  CAS  Google Scholar 

  12. Alberti, S. et al. Neuronal migration in the murine rostral migratory stream requires serum response factor. Proc. Natl. Acad. Sci. USA 102, 6148–6153 (2005).

    Article  CAS  Google Scholar 

  13. Etkin, A. et al. A Role in Learning for SRF: Deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Neuron 50, 127–143 (2006).

    Article  CAS  Google Scholar 

  14. Knoll, B. et al. Serum response factor controls neuronal circuit assembly in the hippocampus. Nat. Neurosci. 9, 195–204 (2006).

    Article  Google Scholar 

  15. Ramanan, N. et al. SRF mediates activity-induced gene expression and synaptic plasticity, but not neuronal viability. Nat. Neurosci. 8, 759–767 (2005).

    Article  CAS  Google Scholar 

  16. Wickramasinghe, S.R. et al. Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58, 532–545 (2008).

    Article  CAS  Google Scholar 

  17. Philippar, U. et al. The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. Mol. Cell 16, 867–880 (2004).

    Article  CAS  Google Scholar 

  18. Sun, Q. et al. Defining the mammalian CArGome. Genome Res. 16, 197–207 (2006).

    Article  CAS  Google Scholar 

  19. Cahoy, J.D. et al. A transcriptome database for astrocytes, neurons and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).

    Article  CAS  Google Scholar 

  20. Dugas, J.C., Tai, Y.C., Speed, T.P., Ngai, J. & Barres, B.A. Functional genomic analysis of oligodendrocyte differentiation. J. Neurosci. 26, 10967–10983 (2006).

    Article  CAS  Google Scholar 

  21. Manke, T., Roider, H.G. & Vingron, M. Statistical modeling of transcription factor binding affinities predicts regulatory interactions. PLoS Comput. Biol. 4, e1000039 (2008).

    Article  Google Scholar 

  22. Roider, H.G., Kanhere, A., Manke, T. & Vingron, M. Predicting transcription factor affinities to DNA from a biophysical model. Bioinformatics 23, 134–141 (2007).

    Article  CAS  Google Scholar 

  23. Erdmann, G., Schutz, G. & Berger, S. Inducible gene inactivation in neurons of the adult mouse forebrain. BMC Neurosci. 8, 63 (2007).

    Article  Google Scholar 

  24. Rivers, L.E. et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat. Neurosci. 11, 1392–1401 (2008).

    Article  CAS  Google Scholar 

  25. Stallcup, W.B. The NG2 proteoglycan: past insights and future prospects. J. Neurocytol. 31, 423–435 (2002).

    Article  CAS  Google Scholar 

  26. Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat. Genet. 33, 366–374 (2003).

    Article  CAS  Google Scholar 

  27. Hulshagen, L. et al. Absence of functional peroxisomes from mouse CNS causes dysmyelination and axon degeneration. J. Neurosci. 28, 4015–4027 (2008).

    Article  CAS  Google Scholar 

  28. McCarthy, K.D. & de Vellis, J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J. Cell Biol. 85, 890–902 (1980).

    Article  CAS  Google Scholar 

  29. Dittgen, T. et al. Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc. Natl. Acad. Sci. USA 101, 18206–18211 (2004).

    Article  CAS  Google Scholar 

  30. Chaqour, B. & Goppelt-Struebe, M. Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J. 273, 3639–3649 (2006).

    Article  CAS  Google Scholar 

  31. Leask, A. & Abraham, D.J. All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J. Cell Sci. 119, 4803–4810 (2006).

    Article  CAS  Google Scholar 

  32. Perbal, B. CCN proteins: multifunctional signaling regulators. Lancet 363, 62–64 (2004).

    Article  CAS  Google Scholar 

  33. Muehlich, S. et al. Actin-dependent regulation of connective tissue growth factor. Am. J. Physiol. Cell Physiol. 292, C1732–C1738 (2007).

    Article  CAS  Google Scholar 

  34. Heuer, H. et al. Connective tissue growth factor: a novel marker of layer VII neurons in the rat cerebral cortex. Neuroscience 119, 43–52 (2003).

    Article  CAS  Google Scholar 

  35. Schratt, G. et al. Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells. J. Cell Biol. 156, 737–750 (2002).

    Article  CAS  Google Scholar 

  36. Vickers, E.R. & Sharrocks, A.D. The use of inducible engrailed fusion proteins to study the cellular functions of eukaryotic transcription factors. Methods 26, 270–280 (2002).

    Article  CAS  Google Scholar 

  37. Ivkovic, S. et al. Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130, 2779–2791 (2003).

    Article  CAS  Google Scholar 

  38. Kim, H.S. et al. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Natl. Acad. Sci. USA 94, 12981–12986 (1997).

    Article  CAS  Google Scholar 

  39. Hsieh, J. et al. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J. Cell Biol. 164, 111–122 (2004).

    Article  CAS  Google Scholar 

  40. McMorris, F.A., Smith, T.M., DeSalvo, S. & Furlanetto, R.W. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development. Proc. Natl. Acad. Sci. USA 83, 822–826 (1986).

    Article  CAS  Google Scholar 

  41. Kuhl, N.M., Hoekstra, D., De Vries, H. & De Keyser, J. Insulin-like growth factor-binding protein 6 inhibits survival and differentiation of rat oligodendrocyte precursor cells. Glia 44, 91–101 (2003).

    Article  Google Scholar 

  42. Ye, P., Carson, J. & D'Ercole, A.J. In vivo actions of insulin-like growth factor-I (IGF-I) on brain myelination: studies of IGF-I and IGF binding protein-1 (IGFBP-1) transgenic mice. J. Neurosci. 15, 7344–7356 (1995).

    Article  CAS  Google Scholar 

  43. Zhou, Q., Choi, G. & Anderson, D.J. The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron 31, 791–807 (2001).

    Article  CAS  Google Scholar 

  44. Lu, Q.R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002).

    Article  CAS  Google Scholar 

  45. Zhou, Q. & Anderson, D.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  CAS  Google Scholar 

  46. Rowitch, D.H. Glial specification in the vertebrate neural tube. Nat. Rev. Neurosci. 5, 409–419 (2004).

    Article  CAS  Google Scholar 

  47. He, Y. et al. The transcription factor Yin Yang 1 is essential for oligodendrocyte progenitor differentiation. Neuron 55, 217–230 (2007).

    Article  CAS  Google Scholar 

  48. Natesan, S. & Gilman, M. YY1 facilitates the association of serum response factor with the c-fos serum response element. Mol. Cell. Biol. 15, 5975–5982 (1995).

    Article  CAS  Google Scholar 

  49. Liu, H. et al. Cysteine-rich protein 61 and connective tissue growth factor induce deadhesion and anoikis of retinal pericytes. Endocrinology 149, 1666–1677 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Schmid for help with GeneChips, J. Berger for electron microscopy, A. Sedlag for excellent student labwork and G. Schütz for the Camk2a-cre mice. We thank M. Jucker, G. Schratt and A. Wizenmann for critically reading the manuscript. B.K. is supported by the DFG Emmy Noether-program, Sonderforschungsbereich 446, the Schram-Stiftung and by young investigator grants from Tübingen University. A.N. is supported by the Deutsche Forschungsgemeinschaft (grant NO 120/12-2).

Author information

Author notes

  1. Christine Stritt, Sina Stern and Kai Harting: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Neuronal Gene Expression Laboratory, Eberhard Karls University Tübingen, Interfaculty Institute for Cell Biology, Tübingen, Germany

    Christine Stritt, Sina Stern, Kai Harting, Daniela Sinske & Bernd Knöll

  2. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany

    Thomas Manke & Martin Vingron

  3. Max Planck Institute for Developmental Biology, Microscopy Unit, Tübingen, Germany

    Heinz Schwarz

  4. Department of Molecular Biology, Molecular Organ Function Laboratory, Eberhard Karls University Tübingen, Interfaculty Institute for Cell Biology, Tübingen, Germany

    Alfred Nordheim

Authors
  1. Christine Stritt
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Sina Stern
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Kai Harting
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Thomas Manke
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Daniela Sinske
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Heinz Schwarz
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Martin Vingron
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Alfred Nordheim
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Bernd Knöll
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

C.S. performed the experiments in Figures 1, 2, 6 and 7, in Supplementary Figures 1,2,3,4,5,6,7 and in Supplementary Tables 1 and 2. S.S. carried out the experiments in Figures 5, 6 and 8, and in Supplementary Figures 2 and 7. K.H. performed the experiments in Figures 4,5,6. B.K. carried out the experiments in Figures 3, 7 and 8. D.S. provided excellent technical assistance throughout. T.M. and M.V. provided bioinformatical analysis. H.S. supervised the electron microscopy. A.N. supplied Srf mutants and co-designed the microarrays. B.K. supervised the study, designed the experiments and wrote the manuscript.

Corresponding author

Correspondence to Bernd Knöll.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 6093 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stritt, C., Stern, S., Harting, K. et al. Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression. Nat Neurosci 12, 418–427 (2009). https://doi.org/10.1038/nn.2280

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2280

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing