Tang Huibin, Goldman Daniel
Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16977-82. doi: 10.1073/pnas.0601565103. Epub 2006 Oct 30.
Muscle activity contributes to muscle development and function largely by means of regulated gene expression. Many genes crucial to neuromuscular synapse formation, such as MuSK and nAChRs, are induced before muscle innervation or after muscle denervation, and this induction requires expression of the E-box binding, basic helix-loop-helix muscle-specific transcription factor, myogenin (Mgn). The mechanism by which muscle activity is coupled to gene expression is poorly defined. Here we report that inhibition of histone deacetylase (HDAC) activity attenuates the induction of activity-regulated genes in aneural myotubes and adult denervated muscle. The effect of HDAC inhibitors requires new protein synthesis, suggesting HDACs may regulate the expression of a Mgn transcriptional repressor. We identified Dach2 as a Mgn transcriptional repressor whose expression is dramatically reduced in an HDAC-dependent manner in developing aneural myotubes or adult denervated muscle. Dach2 overexpression in denervated muscle suppressed Mgn, nAChR, and MuSK gene induction, whereas Dach2 knockdown induced Mgn gene expression in innervated muscle and relieved Mgn promoter inhibition by HDAC inhibitors. Thus, a HDAC-Dach2-myogenin signaling pathway has been identified to decode nerve activity and control muscle gene expression in developing and adult skeletal muscle.
肌肉活动主要通过调控基因表达来促进肌肉发育和功能。许多对神经肌肉突触形成至关重要的基因，如MuSK和nAChRs，在肌肉神经支配之前或肌肉去神经支配之后被诱导表达，而这种诱导需要E盒结合的、碱性螺旋-环-螺旋肌肉特异性转录因子肌细胞生成素（Mgn）的表达。肌肉活动与基因表达偶联的机制尚不清楚。在此，我们报道组蛋白去乙酰化酶（HDAC）活性的抑制减弱了无神经肌管和成年去神经肌肉中活性调节基因的诱导。HDAC抑制剂的作用需要新的蛋白质合成，这表明HDACs可能调节Mgn转录抑制因子的表达。我们鉴定出Dach2作为一种Mgn转录抑制因子，其在发育中的无神经肌管或成年去神经肌肉中以HDAC依赖的方式显著降低表达。在去神经肌肉中过表达Dach2可抑制Mgn、nAChR和MuSK基因的诱导，而敲低Dach2可在神经支配的肌肉中诱导Mgn基因表达，并解除HDAC抑制剂对Mgn启动子的抑制。因此，已鉴定出一条HDAC-Dach2-肌细胞生成素信号通路，以解码神经活动并控制发育中和成年骨骼肌中的肌肉基因表达。
