Paracrine control of oligodendrocyte differentiation by SRF-directed neuronal gene expression.
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.
Stritt
Christine
C
Neuronal Gene Expression Laboratory, Eberhard Karls University Tübingen, Interfaculty Institute for Cell Biology, Department of Molecular Biology, Tübingen, Germany.
Stern
Sina
S
Harting
Kai
K
Manke
Thomas
T
Sinske
Daniela
D
Schwarz
Heinz
H
Vingron
Martin
M
Nordheim
Alfred
A
Knöll
Bernd
B
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004622:Embryo, Mammalian; D015870:Gene Expression / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism; D019899:Paracrine Communication / Q000235:genetics / Q000502:physiology*; D026362:Serum Response Factor / Q000172:deficiency / Q000378:metabolism*
C526318:CCN2 protein, mouse; D009419:Nerve Tissue Proteins; D026362:Serum Response Factor; C519530:insulin-like growth factor-1, mouse; D055513:Connective Tissue Growth Factor; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I