Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2
Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2
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DOI：
10.1101/gad.1338705
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发表时间：
2005-09-01
影响因子：
10.5
通讯作者：
Olson, EN
中科院分区：
文献类型：
--
作者：
Nakagawa, O;Arnold, M;Olson, EN
肌细胞增强因子 2 (MEF2) 在肌肉发育的转录控制中发挥重要作用。然而，作用于 MEF2 下游的信号通路在很大程度上尚不清楚。在这里，我们使用 Mef2c-null 小鼠胚胎进行了微阵列分析，并鉴定了一种新的 MEF2 调节基因，编码肌肉特异性蛋白激酶 Srpk3，属于丝氨酸精氨酸蛋白激酶 (SRPK) 家族，可磷酸化含有丝氨酸/精氨酸重复序列的蛋白质。 Srpk3基因从胚胎发生到成年期在心脏和骨骼肌中特异性表达，并受到MEF2直接调节的肌肉特异性增强子的控制。 Srpk3 缺失小鼠表现出 2 型纤维特异性肌病的新实体，其中位于中央的细胞核显着增加；而骨骼肌中过度表达Srpk3的转基因小鼠表现出严重的肌纤维变性和早期致死。我们得出的结论是，正常的肌肉生长和体内平衡需要 Srpk3 的 MEF2 依赖性信号传导。
Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c-null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.