The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation
The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation
复制标题
DOI：
10.1111/j.1432-0436.2008.00281.x
复制
发表时间：
2008-11-01
期刊：
影响因子：
2.9
通讯作者：
Wevrick, Rachel
中科院分区：
文献类型：
--
作者：
Bush, Jason R.;Wevrick, Rachel
肌肉前体的增殖和分化受肌肉特异性基因的激活和分化抑制物的失活控制。Necdin是一种多功能蛋白，在神经和肌源性分化过程中上调。Necdin在发育过程中促进细胞周期退出和分化，但Necdin在胚胎肌肉发生中的作用尚未被描述。在细胞质双杂交筛选中，我们确定了Necdin和E1a样分化抑制因子(EID-1)之间的一种新的相互作用。EID-1抑制成肌分化所需基因的转录激活，并在细胞周期退出时在成肌细胞中降解。在反式激活试验中，在MyoD存在的情况下，Necdin对myoD反应启动子没有直接影响，但Necdin确实解除了这些启动子对EID-1的依赖抑制。在活体内，来自先天缺陷症小鼠胚胎的原代胚胎肢芽培养中存在正常数量的MyoD表达的成肌细胞。相反，与野生型对照相比，培养5天的分化肢芽培养物中表达肌球蛋白重链的肌管数量减少。在Necdin的存在下，EID-1的稳态水平增加，半衰期延长，当Necdin在细胞内共表达时，EID-1从细胞核重新定位到细胞质。总而言之，这些数据与一个模型是一致的，在该模型中，Necdin至少部分地通过缓解EID-1的抑制作用来促进成肌细胞分化。
Proliferation and differentiation of muscle precursors are controlled by the activation of muscle-specific genes and inactivation of inhibitors of differentiation. Necdin is a multi-functional protein that is up-regulated during neural and myogenic differentiation. Necdin facilitates cell cycle exit and differentiation during development, but the role of necdin in embryonic myogenesis has not been described. In a cytoplasmic two-hybrid screen, we identified a novel interaction between necdin and the E1A-like inhibitor of differentiation (EID-1). EID-1 inhibits transcriptional activation of genes required for myogenic differentiation, and is degraded in myoblasts upon cell cycle exit. In a transactivation assay, necdin had no direct effect on myoD-responsive promoters in the presence of MyoD, but necdin did relieve the EID-1-dependent inhibition of these same promoters. In vivo, a normal number of MyoD-expressing myoblasts was present in primary embryonic limb bud cultures from mouse embryos with congenital necdin deficiency. In contrast, the number of myosin heavy chain-expressing myotubes in differentiating limb bud cultures cultured for 5 days was reduced compared with cultures from wild-type littermate controls. In the presence of necdin, steady-state levels of EID-1 were increased and the half-life of EID-1 was extended, and EID-1 was re-localized from the nucleus to the cytoplasm when necdin was co-expressed in transfected cells. Collectively, these data are consistent with a model whereby necdin promotes myoblast differentiation at least in part by relieving the inhibitory effect of EID-1.