Department of Molecular Biology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Development. 2010 Jul;137(14):2365-74. doi: 10.1242/dev.047605. Epub 2010 Jun 9.
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.
许多运动细胞的功能依赖于细胞骨架向细胞核的信号传递。肌球蛋白相关转录因子（MRTFs）在肌动蛋白聚合的作用下易位到细胞核，并与血清反应因子（Srf）合作，调节编码肌动蛋白和细胞骨架其他成分的基因的表达。在这里，我们表明 MRTF-A（Mkl1）和 MRTF-B（Mkl2）在小鼠大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 共激活因子的基因的条件缺失破坏了多个脑结构的形成，反映了神经元肌动蛋白聚合和细胞骨架组装的失败。这些异常伴随着肌动蛋白切割蛋白gelsolin 和 Pctaire1（Cdk16）激酶的失调，它们与 Cdk5 合作启动激酶级联反应，该反应控制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 伙伴关系将两个关键信号通路联系起来，这些信号通路控制肌动蛋白的 treadmilling 和神经元成熟，从而完成一个调节环，在大脑发育过程中，将细胞骨架动力学与核基因转录联系起来。
