Zac1/GPR39 phosphorylating CaMK-II contributes to the distinct roles of Pax3 and Pax7 in myogenic progression
Zac1/GPR39 phosphorylating CaMK-II contributes to the distinct roles of Pax3 and Pax7 in myogenic progression
复制标题
Zac1/GPR39 磷酸化 CaMK-II 有助于 Pax3 和 Pax7 在肌源性进展中的独特作用
DOI：
10.1016/j.bbadis.2017.10.026
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Daiwen Chen
中科院分区：
文献类型：
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作者：
Qiumei Yang;Ye Li;Xulong Zhang;Daiwen Chen
Pax 3和Pax 7都可以激活参与肌肉干细胞功能的大量基因。尽管在它们的转录网络中有显著的重叠，但观察到它们之间的功能差异。在C2 C12中过表达Pax 3或Pax 7后，我们发现Pax 7上调Zac 1和GPR 39，但不上调Pax 3。进一步的研究表明，Zac 1直接与Pax 7相互作用，Pax 7可以通过激活Zac 1来调节GPR 39的表达。此外，Zac 1/GPR 39系统对肌源性进展的影响已被阐明：Zac 1/GPR 39可促进肌源性分化并产生II型肌纤维。步态分析验证了将GFP标记的Pax 7 RV/siZac 1转染细胞移植到肌肉损伤的mdx小鼠中会延迟肌肉功能的修复。分子机制研究表明，Zac 1/GPR 39系统与Pax 3和Pax 7不同的成肌功能有关：Pax 7激活Zac 1/GPR 39，介导CaMK-Ⅱ磷酸化，导致p-ERK 1/2去磷酸化和β-catenin抑制，促进II型肌纤维形成;缺乏Zac 1/GPR 39系统的细胞在诱导分化后倾向于保持干细胞并形成I型肌纤维。本研究将有助于更好地了解Pax 3和Pax 7在肌源性进展和肌纤维类型调节中的分子机制，为肌肉疾病的治疗提供合适的靶点。
Both Pax3 and Pax7 can activate a large panel of genes involved in muscle stem cell function. Despite a significant overlap in their transcriptional network, functional difference between them is observed. After overexpressing Pax3 or Pax7 in C2C12, we find both Zac1 and GPR39 are upregulated by Pax7 but not Pax3. Further studies suggest Zac1 interacts directly with Pax7, which can regulate GPR39 expression by activating Zac1. In addition, the effect of Zac1/GPR39 system on myogenic progression has been illuminated: Zac1/GPR39 can promote myogenic differentiation and produce type-II muscle fibers. Gait analysis verifies that transplanting GFP-labeled Pax7 RV/siZac1 transfected cells into mdx mice with muscle injury would delay muscle function repair. Molecular mechanism studies reveal the Zac1/GPR39 system is associated with different myogenic functions of Pax3 and Pax7: Pax7 activates Zac1/GPR39, which mediates the phosphorylation of CaMK-II, resulting in p-ERK1/2 dephosphorylation and β-catenin inhibition, that promotes the formation of type-II muscle fibers; cells lacking Zac1/GPR39 system tend to remain stemness and form type-I muscle fibers after induced differentiation. This study will help the better understanding of the molecular mechanism of Pax3 and Pax7 in the regulation of myogenic progression and muscle fiber types, laying the providing suitable targets for the treatment of muscle diseases.