Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development.
Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development.
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Msx1 磷酸化在胚胎肢体发育过程中通过 Fgf9/18-MAPK 信号通路促进细胞增殖
DOI：
10.1093/nar/gkaa905
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发表时间：
2020-11-18
影响因子：
14.9
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Yang Y;Zhu X;Jia X;Hou W;Zhou G;Ma Z;Yu B;Pi Y;Zhang X;Wang J;Wang G
摘要MSH Homeobox(MSX)是同源盒转录调控因子的一个亚类，它控制细胞谱系的发育，包括脊椎动物肢体发育的早期，尽管其潜在的机制尚不清楚。在这里，我们证明Msx1通过增强丝裂原活化蛋白激酶(MAPK)信号通路促进成肌细胞和间充质干细胞(MSCs)的增殖。Msx1直接结合并上调成纤维细胞生长因子9(Fgf9)和Fgf18的表达。因此，Fgf9/18的敲除或抗体中和抑制了Msx1激活的细胞外信号调节蛋白1/2(ERK1/2)的磷酸化。机制上，我们确定Ser136位Msx1的磷酸化是促进Fgf9和Fgf18表达和细胞增殖的关键，而细胞周期蛋白依赖性激酶1(CDK1)显然与Ser136的磷酸化有关。此外，Msx1/2间充质缺失导致Fgf9和Fgf18表达降低，ERK1/2磷酸化，导致小鼠肢体发育严重缺陷。总之，我们的发现确立了Msx1-FGF-MAPK信号轴在促进细胞增殖中的重要作用，从而为肢体发育提供了新的机制见解。
Abstract Msh homeobox (Msx) is a subclass of homeobox transcriptional regulators that control cell lineage development, including the early stage of vertebrate limb development, although the underlying mechanisms are not clear. Here, we demonstrate that Msx1 promotes the proliferation of myoblasts and mesenchymal stem cells (MSCs) by enhancing mitogen-activated protein kinase (MAPK) signaling. Msx1 directly binds to and upregulates the expression of fibroblast growth factor 9 (Fgf9) and Fgf18. Accordingly, knockdown or antibody neutralization of Fgf9/18 inhibits Msx1-activated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Mechanistically, we determined that the phosphorylation of Msx1 at Ser136 is critical for enhancing Fgf9 and Fgf18 expression and cell proliferation, and cyclin-dependent kinase 1 (CDK1) is apparently responsible for Ser136 phosphorylation. Furthermore, mesenchymal deletion of Msx1/2 results in decreased Fgf9 and Fgf18 expression and Erk1/2 phosphorylation, which leads to serious defects in limb development in mice. Collectively, our findings established an important function of the Msx1-Fgf-MAPK signaling axis in promoting cell proliferation, thus providing a new mechanistic insight into limb development.
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影响因子：
2.7
作者：
Cornelison, DDW;Olwin, BB;Wold, BJ
通讯作者：
Wold, BJ
影响因子：
4.8
作者：
Heller, H;Gredinger, E;Bengal, E
通讯作者：
Bengal, E
DOI：
10.1016/j.bbamcr.2012.05.018
发表时间：
2012-08-01
影响因子：
5.1
作者：
Jeong, Hyung Min;Jin, Yun-Hye;Lee, Kwang-Youl
通讯作者：
Lee, Kwang-Youl
影响因子：
3.7
作者：
Danopoulos S;Parsa S;Al Alam D;Tabatabai R;Baptista S;Tiozzo C;Carraro G;Wheeler M;Barreto G;Braun T;Li X;Hajihosseini MK;Bellusci S
通讯作者：
Bellusci S
影响因子：
13.8
作者：
Holmberg, CI;Tran, SEF;Sistonen, L
通讯作者：
Sistonen, L