Knöll Bernd, Kretz Oliver, Fiedler Christine, Alberti Siegfried, Schütz Günther, Frotscher Michael, Nordheim Alfred
Interfakultäres Institut für Zellbiologie, Abt. Molekularbiologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
Nat Neurosci. 2006 Feb;9(2):195-204. doi: 10.1038/nn1627. Epub 2006 Jan 15.
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.
高等生物依靠海马体网络采用多种记忆存储模式，海马体网络是由轴突生长、导向和突触靶向的精确协调机制构建而成。我们证明了转录因子血清反应因子（SRF），一种细胞骨架肌动蛋白动力学的传感器，在所有这些过程中都起着至关重要的作用。小鼠Srf基因的条件性缺失减少了神经突的生长并消除了苔藓纤维的分离，导致锥体层内出现异位纤维生长。SRF缺陷的苔藓纤维异常地靶向CA3体细胞以形成突触。轴突导向试验表明，SRF是ephrin-A和信号素导向线索的关键介导因子；在SRF缺陷的神经元中，这些导向线索导致形成F-肌动蛋白-微管环，而不是完全的生长锥塌陷。SRF辅因子巨核细胞急性白血病（MAL）的显性负变体严重阻碍了神经突的生长和导向。这些数据突出了SRF介导的转录与海马体中轴突导向和回路形成之间的重要联系。
