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Serum response factor controls neuronal circuit assembly in the hippocampus

Nature Neuroscience volume 9, pages 195–204 (2006)Cite this article

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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Figure 2: Aberrant synaptic targeting of SRF-deficient mossy fiber terminals.
Figure 8: Identification of putative Srf target genes in hippocampal neurons.
Figure 1: Srf mutants show hippocampal neurite loss and mossy fiber misrouting in vivo.
Figure 3: Srf mutants show impaired neurite outgrowth.
Figure 4: Overexpression of SRF-VP16 promotes neurite elongation.
Figure 5: SRF is required for contact-mediated, repulsive axon guidance in vitro.
Figure 6: Growth cone dynamics are severely impaired in Srf mutants.
Figure 7: Rho-GTPase activity and the function of the SRF cofactor MAL in hippocampal neurons.

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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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Authors and Affiliations

  1. Interfakultäres Institut für Zellbiologie, Abt. Molekularbiologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 15, Tübingen, 72076, Germany

    Bernd Knöll, Christine Fiedler, Siegfried Alberti & Alfred Nordheim

  2. Institut für Anatomie und Zellbiologie, Albert-Ludwigs-Universität Freiburg, Freiburg, 79104, Germany

    Oliver Kretz & Michael Frotscher

  3. Deutsches Krebsforschungszentrum (DKFZ), Molekularbiologie der Zelle I, Heidelberg, Germany

    Günther Schütz

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Correspondence to Alfred Nordheim.

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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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