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

Stritt, Christine; Stern, Sina; Harting, Kai; Manke, Thomas; Sinske, Daniela; Schwarz, Heinz; Vingron, Martin; Nordheim, Alfred; Knöll, Bernd

doi:10.1038/nn.2280

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

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Manke, Thomas
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

Schwarz, Heinz
Max Planck Society;

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Vingron, Martin
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Stritt, C., Stern, S., Harting, K., Manke, T., Sinske, D., Schwarz, H., et al. (2009). Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression. Nature Neuroscience, 12(4), 418-427. doi:10.1038/nn.2280.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-7DF9-9

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.