Serum response factor controls neuronal circuit assembly in the hippocampus.
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.
Knöll
Bernd
B
Interfakultäres Institut für Zellbiologie, Abt. Molekularbiologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
Kretz
Oliver
O
Fiedler
Christine
C
Alberti
Siegfried
S
Schütz
Günther
G
Frotscher
Michael
M
Nordheim
Alfred
A
D000199:Actins / Q000378:metabolism; D000818:Animals; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D000099251:Myocardin
D000199:Actins; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin