Neville C M, Choe Y H, Lee Y S, Spinner D, Tsay H J, Schmidt J
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129-2060, USA.
J Biol Chem. 1998 May 29;273(22):14046-52. doi: 10.1074/jbc.273.22.14046.
Motor activity blocks the extrasynaptic expression of many genes in skeletal muscle, including those encoding ion channels, receptors, and adhesion molecules. Denervation reinduces transcription throughout the multinucleated myofiber, restoring the developmental pattern of expression, especially of the genes coding for the acetylcholine receptor. A screen for trans-acting factors binding to the enhancer region of the alpha-subunit gene of the acetylcholine receptor identified CTF4, a ubiquitously expressed and alternatively spliced chicken homologue of the human E protein transcription factor HTF4/HEB. Expression of the CTF4 locus closely parallels that of myogenin and acetylcholine receptor during development and maturation of skeletal muscle, but transcription is not similarly regulated by neuronal cues. Alternative splicing within the region encoding the transactivation domain generates two CTF4 isoforms with different tissue distributions, but similar binding affinities for the acetylcholine receptor alpha-subunit enhancer and similar transcriptional potential when complexed to myogenin. Direct injection of a myogenin, but not a MyoD, antisense expression vector into denervated skeletal muscle caused a significant decrease in the transcriptional activation of a depolarization-sensitive reporter gene. Similarly, injection of a CTF4, but less so of an E12, antisense expression vector impaired the denervation response, further implicating the involvement of a myogenin/CTF4 heterodimer in the expression of AChR genes in vivo.
运动活动会阻断骨骼肌中许多基因的突触外表达，包括那些编码离子通道、受体和黏附分子的基因。去神经支配会在整个多核肌纤维中重新诱导转录，恢复发育过程中的表达模式，尤其是编码乙酰胆碱受体的基因的表达模式。一项针对与乙酰胆碱受体α亚基基因增强子区域结合的反式作用因子的筛选，鉴定出了CTF4，它是人类E蛋白转录因子HTF4/HEB在鸡体内普遍表达且可变剪接的同源物。在骨骼肌发育和成熟过程中，CTF4基因座的表达与肌细胞生成素和乙酰胆碱受体的表达密切平行，但转录不受神经元信号的类似调控。在编码反式激活结构域的区域内的可变剪接产生了两种具有不同组织分布的CTF4异构体，但它们对乙酰胆碱受体α亚基增强子具有相似的结合亲和力，并且与肌细胞生成素复合时具有相似的转录潜能。将肌细胞生成素而非MyoD的反义表达载体直接注射到去神经支配的骨骼肌中，会导致去极化敏感报告基因的转录激活显著降低。同样，注射CTF4反义表达载体（注射E12反义表达载体的效果稍差）会损害去神经支配反应，这进一步表明肌细胞生成素/CTF4异二聚体在体内参与乙酰胆碱受体基因的表达。
