Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration
Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration
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DOI：
10.1093/hmg/ddi479
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发表时间：
2006-02-15
影响因子：
3.5
通讯作者：
Stewart, CL
中科院分区：
文献类型：
--
作者：
Melcon, G;Kozlov, S;Stewart, CL
Emery-Dreifuss肌营养不良症（EDMD 1）是由X连锁基因emerin（EMD）或常染色体核纤层蛋白A/C（LMNA）基因突变引起的。在这里，我们描述了小鼠缺乏emerin的推导，试图推导出EDMD 1的小鼠模型。虽然缺乏Emerin的小鼠没有明显的病理学表现，但这些小鼠的肌肉再生显示出缺陷。再生Emd空肌肉的生物信息学阵列分析显示细胞周期参数异常和延迟的肌源性分化，这与视网膜母细胞瘤（Rb 1）和MyoD基因调控的转录途径的扰动有关。MyoD转录靶点的时间激活显著延迟，而Rb 1/E2 F转录抑制因子复合物的靶点仍然不适当地活跃。Rb 1/MyoD转录靶点的不适当调节与Rb 1、MyoD及其共激活物/抑制物转录物的上调相关，表明在再生过程中，在成肌细胞/肌管过渡期克服分化的分子阻滞是一种补偿性努力。这种补偿似乎对MyoD转录靶点有效，尽管对Rb 1靶点不太有效。Rb 1磷酸化状态的分析表明，在Emd空肌源性细胞的关键发育阶段，在体内和体外延长的过度磷酸化。我们还分析了Lmna无效肌肉中的相同途径，其显示广泛的营养不良。令人惊讶的是，Lmna空肌肉没有表现出相同的扰动Rb和MyoD依赖性途径。我们确实观察到Lap 2 α的转录表达增加和Rb 1的延迟表达，这可能调节Lmna缺失成肌细胞中的替代转录途径。我们认为，在许多临床上不同的核纤层蛋白病中观察到的显性LMNA突变可能类似地改变Rb功能，关于退出细胞周期或终末分化程序或两者的时间。
Emery-Dreifuss muscular dystrophy (EDMD1) is caused by mutations in either the X-linked gene emerin (EMD) or the autosomal lamin A/C (LMNA) gene. Here, we describe the derivation of mice lacking emerin in an attempt to derive a mouse model for EDMD1. Although mice lacking emerin show no overt pathology, muscle regeneration in these mice revealed defects. A bioinformatic array analysis of regenerating Emd null muscle revealed abnormalities in cell-cycle parameters and delayed myogenic differentiation, which were associated with perturbations to transcriptional pathways regulated by the retinoblastoma (Rb1) and MyoD genes. Temporal activation of MyoD transcriptional targets was significantly delayed, whereas targets of the Rb1/E2F transcriptional repressor complex remained inappropriately active. The inappropriate modulation of Rb1/MyoD transcriptional targets was associated with up-regulation of Rb1, MyoD and their co-activators/repressors transcripts, suggesting a compensatory effort to overcome a molecular block to differentiation at the myoblast/myotube transition during regeneration. This compensation appeared to be effective for MyoD transcriptional targets, although was less effective for Rb1 targets. Analysis of Rb1 phosphorylation states showed prolonged hyper-phosphorylation at key developmental stages in Emd null myogenic cells, both in vivo and in vitro. We also analyzed the same pathways in Lmna null muscle, which shows extensive dystrophy. Surprisingly, Lmna null muscle did not show the same perturbations to Rb- and MyoD-dependent pathways. We did observe increased transcriptional expression of Lap2 alpha and delayed expression of Rb1, which may regulate alternative transcriptional pathways in the Lmna null myoblasts. We suggest that the dominant LMNA mutations seen in many clinically disparate laminopathies may similarly alter Rb function, with regard to either the timing of exit from the cell cycle or terminal differentiation programs or both.