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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.

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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.

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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).

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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

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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.

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Correspondence to Bernd Knöll.

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

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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

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