Eberhard-Karls-Universität Tübingen, Interfaculty Institute for Cell Biology, Department of Molecular Biology, Neuronal Gene Expression Laboratory, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
Mol Cell Biol. 2010 Apr;30(7):1828-37. doi: 10.1128/MCB.01434-09. Epub 2010 Feb 1.
During brain development, neurons and their nerve fibers are often segregated in specific layers. The hippocampus is a well-suited model system to study lamination in health and aberrant cell/fiber lamination associated with neurological disorders. SRF (serum response factor), a transcription factor, regulates synaptic-activity-induced immediate-early gene (IEG) induction and cytoskeleton-based neuronal motility. Using early postnatal conditional SRF ablation, we uncovered distorted hippocampal lamination, including malpositioning of granule cell neurons and disruption of layer-restricted termination of commissural-associational and mossy fiber axons. Besides axons, dendrite branching and spine morphogenesis in Srf mutants were impaired, offering a first morphological basis for SRF's reported role in learning and memory. Srf mutants resemble mice lacking components of the reelin signaling cascade, a fundamental signaling entity in brain lamination. Our data indicate that reelin signaling and SRF-mediated gene transcription might be connected: reelin induces IEG and cytoskeletal genes in an SRF-dependent manner. Further, reelin-induced neurite motility is blocked in Srf mutants and constitutively active SRF rescues impaired neurite extension in reeler mouse mutants in vitro. In sum, data provided in this report show that SRF contributes to hippocampal layer and nerve fiber organization and point at a link between Srf gene transcription and reelin signaling.
在大脑发育过程中，神经元及其神经纤维通常会在特定的层中分离。海马体是研究健康分层以及与神经紊乱相关的异常细胞/纤维分层的理想模型系统。SRF（血清反应因子）是一种转录因子，可调节突触活动诱导的即时早期基因（IEG）诱导和基于细胞骨架的神经元迁移。通过早期出生后条件性 SRF 消融，我们发现海马体分层发生扭曲，包括颗粒细胞神经元位置错位以及联合/苔藓纤维轴突的层限制终止中断。除了轴突，Srf 突变体中的树突分支和棘突形态发生也受损，为 SRF 在学习和记忆中的作用提供了第一个形态学基础。Srf 突变体类似于缺乏 reelin 信号级联成分的小鼠，reelin 是大脑分层的基本信号实体。我们的数据表明，reelin 信号和 SRF 介导的基因转录可能存在联系：reelin 以依赖于 SRF 的方式诱导 IEG 和细胞骨架基因。此外，reelin 诱导的神经突迁移在 Srf 突变体中受阻，而组成型激活的 SRF 可挽救 reeler 小鼠突变体外神经突延伸受损。总之，本报告提供的数据表明，SRF 有助于海马体的分层和神经纤维组织，并指出了 Srf 基因转录和 reelin 信号之间的联系。
