Abstract:
Serum response factor (SRF) is an essential transcription factor for brain development and function. Here, we explored how an SRF cofactor, the actin monomer-sensing myocardin-related transcription factor MRTF, is regulated in mouse cortical neurons. We found that MRTF-dependent SRF activity in vitro and in vivo was repressed by cyclase-associated protein CAP1. Inactivation of the actin-binding protein CAP1 reduced the amount of actin monomers in the cytoplasm, which promoted nuclear MRTF translocation and MRTF-SRF activation. This function was independent of cofilin1 and actin-depolymerizing factor, and CAP1 loss of function in cortical neurons was not compensated by endogenous CAP2. Transcriptomic and proteomic analyses of cerebral cortex lysates from wild-type and Cap1 knockout mice supported the role of CAP1 in repressing MRTF-SRF-dependent signaling in vivo. Bioinformatic analysis identified likely MRTF-SRF target genes, which aligned with the transcriptomic and proteomic results. Together with our previous studies that implicated CAP1 in axonal growth cone function as well as the morphology and plasticity of excitatory synapses, our findings establish CAP1 as a crucial actin regulator in the brain relevant for formation of neuronal networks.
摘要:
血清反应因子(SRF)是脑发育和功能必需的转录因子。这里,我们探索了SRF辅因子,肌动蛋白单体感应心肌相关转录因子MRTF,在小鼠皮层神经元中被调节。我们发现,环化酶相关蛋白CAP1抑制了MRTF依赖性SRF的体外和体内活性。肌动蛋白结合蛋白CAP1的失活减少了细胞质中肌动蛋白单体的数量,促进核MRTF易位和MRTF-SRF激活。该功能与cofilin1和肌动蛋白解聚因子无关,和CAP1皮质神经元功能的丧失没有被内源性CAP2补偿。来自野生型和Cap1敲除小鼠的大脑皮层裂解物的转录组学和蛋白质组学分析支持CAP1在体内抑制MRTF-SRF依赖性信号传导中的作用。生物信息学分析确定了可能的MRTF-SRF靶基因,与转录组学和蛋白质组学结果一致。结合我们先前的研究,CAP1涉及轴突生长锥功能以及兴奋性突触的形态和可塑性,我们的发现证明CAP1是大脑中与神经元网络形成相关的重要肌动蛋白调节因子.