Edmondson D G, Cheng T C, Cserjesi P, Chakraborty T, Olson E N
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Mol Cell Biol. 1992 Sep;12(9):3665-77. doi: 10.1128/mcb.12.9.3665-3677.1992.
Transcriptional cascades that specify cell fate have been well described in invertebrates. In mammalian development, however, gene hierarchies involved in determination of cell lineage are not understood. With the recent cloning of the MyoD family of myogenic regulatory factors, a model system has become available with which to study the dynamics of muscle determination in mammalian development. Myogenin, along with other members of the MyoD gene family, possesses the apparent ability to redirect nonmuscle cells into the myogenic lineage. This ability appears to be due to the direct activation of an array of subordinate or downstream genes which are responsible for formation and function of the muscle contractile apparatus. Myogenin-directed transcription has been shown to occur through interaction with a DNA consensus sequence known as an E box (CANNTG) present in the control regions of numerous downstream genes. In addition to activating the transcription of subordinate genes, members of the MyoD family positively regulate their own expression and cross-activate one another's expression. These autoregulatory interactions have been suggested as a mechanism for induction and maintenance of the myogenic phenotype, but the molecular details of the autoregulatory circuits are undefined. Here we show that the myogenin promoter contains a binding site for the myocyte-specific enhancer-binding factor, MEF-2, which can function as an intermediary of myogenin autoactivation. Since MEF-2 can be induced by myogenin, these results suggest that myogenin and MEF-2 participate in a transcriptional cascade in which MEF-2, once induced by myogenin, acts to amplify and maintain the myogenic phenotype by acting as a positive regulator of myogenin expression.
在无脊椎动物中，决定细胞命运的转录级联反应已得到充分描述。然而，在哺乳动物发育过程中，参与细胞谱系确定的基因层次结构尚不清楚。随着肌源性调节因子MyoD家族最近的克隆成功，一个用于研究哺乳动物发育中肌肉决定动态的模型系统得以建立。肌细胞生成素与MyoD基因家族的其他成员一起，具有将非肌肉细胞重定向到肌源性谱系的明显能力。这种能力似乎是由于一系列负责肌肉收缩装置形成和功能的从属或下游基因的直接激活。已证明肌细胞生成素指导的转录是通过与存在于众多下游基因控制区域的称为E盒（CANNTG）的DNA共有序列相互作用而发生的。除了激活从属基因的转录外，MyoD家族成员还正向调节它们自身的表达并相互交叉激活彼此的表达。这些自调节相互作用被认为是诱导和维持肌源性表型的一种机制，但自调节回路的分子细节尚不清楚。在这里，我们表明肌细胞生成素启动子含有一个肌细胞特异性增强子结合因子MEF-2的结合位点，它可以作为肌细胞生成素自激活的中介。由于MEF-2可被肌细胞生成素诱导，这些结果表明肌细胞生成素和MEF-2参与了一个转录级联反应，其中MEF-2一旦被肌细胞生成素诱导，就通过作为肌细胞生成素表达的正向调节因子来放大和维持肌源性表型。
