Abstract
Higher organisms rely on multiple modes of memory storage using the hippocampal network, which is built by precisely orchestrated mechanisms of axonal outgrowth, guidance and synaptic targeting. We demonstrate essential roles of the transcription factor serum response factor (SRF), a sensor of cytoskeletal actin dynamics, in all these processes. Conditional deletion of the mouse Srf gene reduced neurite outgrowth and abolished mossy fiber segregation, resulting in ectopic fiber growth inside the pyramidal layer. SRF-deficient mossy fibers aberrantly targeted CA3 somata for synapse formation. Axon guidance assays showed that SRF was a key mediator of ephrin-A and semaphorin guidance cues; in SRF-deficient neurons, these resulted in the formation of F-actin–microtubule rings rather than complete growth cone collapse. Dominant-negative variants of the SRF cofactor megakaryocytic acute leukemia (MAL) severely impeded neurite outgrowth and guidance. These data highlight essential links between SRF-mediated transcription and axon guidance and circuit formation in the hippocampus.
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Acknowledgements
We thank B. Habermehl, M. Koch, B. Joch and D. Steuerwald for experimental help and T. Skutella for discussions. We received financial aid from the Deutsche Forschungsgemeinschaft (120/12-1, SFB 446 and SFB 505) and the Fonds der Chemischen Industrie.
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Supplementary information
Supplementary Fig. 1
Expression profile of Srf RNA in the hippocampal system (PDF 6757 kb)
Supplementary Fig. 2
Identification of presynaptic cells with immunoelectron microscopy in Srf mutants (PDF 9046 kb)
Supplementary Fig. 3
SRF contributes to neuronal polarization (PDF 12579 kb)
Supplementary Fig. 4
Actin cannot fully compensate for SRF deficiency (PDF 10758 kb)
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Knöll, B., Kretz, O., Fiedler, C. et al. Serum response factor controls neuronal circuit assembly in the hippocampus. Nat Neurosci 9, 195–204 (2006). https://doi.org/10.1038/nn1627
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DOI: https://doi.org/10.1038/nn1627
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