Myocardin-related transcription factors regulate the Cdk5/Pctaire1 kinase cascade to control neurite outgrowth, neuronal migration and brain development
Myocardin-related transcription factors regulate the Cdk5/Pctaire1 kinase cascade to control neurite outgrowth, neuronal migration and brain development
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DOI：
10.1242/dev.047605
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发表时间：
2010-07-15
期刊：
影响因子：
4.6
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Mokalled, Mayssa H.;Johnson, Aaron;Olson, Eric N.
细胞的许多运动功能依赖于从细胞骨架到细胞核的信号传递。肌钙蛋白相关转录因子(MRTF)在肌动蛋白聚合反应中转位到细胞核，并与血清反应因子(SRF)协同调节肌动蛋白编码基因和其他细胞骨架成分的表达。在这里，我们证明了MRTF-A(MKL1)和MRTF-B(MKL2)在小鼠脑发育过程中冗余地控制神经元迁移和轴突生长。编码这些SRF共激活子的基因的条件性缺失扰乱了多种大脑结构的形成，反映了神经元肌动蛋白聚合和细胞骨架组装的失败。伴随着这些异常的是肌动蛋白切断蛋白明胶蛋白和Pctaire1(CDK16)激酶的失调，该蛋白与CDK5协同启动了一种激酶级联反应，从而调控了对神经元迁移和轴突生长至关重要的细胞骨架重排。因此，MRTF/SRF伙伴关系将控制肌动蛋白踏步和神经元成熟的两个关键信号通路连接在一起，从而实现了脑发育过程中细胞骨架动力学与核基因转录之间的调节环路。
Numerous motile cell functions depend on signaling from the cytoskeleton to the nucleus. Myocardin-related transcription factors (MRTFs) translocate to the nucleus in response to actin polymerization and cooperate with serum response factor (Srf) to regulate the expression of genes encoding actin and other components of the cytoskeleton. Here, we show that MRTF-A (Mkl1) and MRTF-B (Mkl2) redundantly control neuronal migration and neurite outgrowth during mouse brain development. Conditional deletion of the genes encoding these Srf coactivators disrupts the formation of multiple brain structures, reflecting a failure in neuronal actin polymerization and cytoskeletal assembly. These abnormalities were accompanied by dysregulation of the actin-severing protein gelsolin and Pctaire1 (Cdk16) kinase, which cooperates with Cdk5 to initiate a kinase cascade that governs cytoskeletal rearrangements essential for neuron migration and neurite outgrowth. Thus, the MRTF/Srf partnership interlinks two key signaling pathways that control actin treadmilling and neuronal maturation, thereby fulfilling a regulatory loop that couples cytoskeletal dynamics to nuclear gene transcription during brain development.