Cenik Bercin K, Liu Ning, Chen Beibei, Bezprozvannaya Svetlana, Olson Eric N, Bassel-Duby Rhonda
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA The Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Development. 2016 Aug 1;143(15):2853-61. doi: 10.1242/dev.135855. Epub 2016 Jul 6.
Myocardin-related transcription factors (MRTFs) play a central role in the regulation of actin expression and cytoskeletal dynamics. Stimuli that promote actin polymerization allow for shuttling of MRTFs to the nucleus where they activate serum response factor (SRF), a regulator of actin and other cytoskeletal protein genes. SRF is an essential regulator of skeletal muscle differentiation and numerous components of the muscle sarcomere, but the potential involvement of MRTFs in skeletal muscle development has not been examined. We explored the role of MRTFs in muscle development in vivo by generating mutant mice harboring a skeletal muscle-specific deletion of MRTF-B and a global deletion of MRTF-A. These double knockout (dKO) mice were able to form sarcomeres during embryogenesis. However, the sarcomeres were abnormally small and disorganized, causing skeletal muscle hypoplasia and perinatal lethality. Transcriptome analysis demonstrated dramatic dysregulation of actin genes in MRTF dKO mice, highlighting the importance of MRTFs in actin cycling and myofibrillogenesis. MRTFs were also shown to be necessary for the survival of skeletal myoblasts and for the efficient formation of intact myotubes. Our findings reveal a central role for MRTFs in sarcomere formation during skeletal muscle development and point to the potential involvement of these transcriptional co-activators in skeletal myopathies.
心肌相关转录因子（MRTFs）在肌动蛋白表达和细胞骨架动力学调节中发挥核心作用。促进肌动蛋白聚合的刺激因素可使MRTFs穿梭至细胞核，在细胞核中它们激活血清反应因子（SRF），SRF是肌动蛋白和其他细胞骨架蛋白基因的调节因子。SRF是骨骼肌分化和肌节众多成分的重要调节因子，但MRTFs在骨骼肌发育中的潜在作用尚未得到研究。我们通过构建骨骼肌特异性缺失MRTF-B和全身性缺失MRTF-A的突变小鼠，探索了MRTFs在体内肌肉发育中的作用。这些双敲除（dKO）小鼠在胚胎发生过程中能够形成肌节。然而，这些肌节异常小且排列紊乱，导致骨骼肌发育不全和围产期致死。转录组分析表明，MRTF dKO小鼠中肌动蛋白基因存在显著失调，突出了MRTFs在肌动蛋白循环和肌原纤维生成中的重要性。MRTFs对于骨骼肌成肌细胞的存活以及完整肌管的有效形成也是必需的。我们的研究结果揭示了MRTFs在骨骼肌发育过程中肌节形成中的核心作用，并指出这些转录共激活因子可能参与骨骼肌疾病。
