Laminin and Matrix metalloproteinase 11 regulate Fibronectin levels in the zebrafish myotendinous junction.
Laminin and Matrix metalloproteinase 11 regulate Fibronectin levels in the zebrafish myotendinous junction.
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DOI：
10.1186/s13395-016-0089-3
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发表时间：
2016
期刊：
影响因子：
4.9
通讯作者：
Henry CA
中科院分区：
文献类型：
--
作者：
Jenkins MH;Alrowaished SS;Goody MF;Crawford BD;Henry CA
细胞外基质 (ECM) 的重塑可调节细胞粘附以及细胞与其微环境之间的信号传导。尽管严格调控的 ECM 重塑对于正常肌肉发育和功能非常重要，但体内 ECM 重塑的机制仍然难以捉摸。研究体内 ECM 重塑的一个很好的范例是斑马鱼骨骼肌发育过程中肌腱连接处 (MTJ) 的形态发生。在 MTJ 开发过程中，组成 MTJ 矩阵的主要组件发生了巨大的变化。其中一种转变涉及用富含层粘连蛋白的基质替换对体节和早期肌肉发育至关重要的富含纤连蛋白 (Fn) 的基质，这对肌节的正常功能至关重要。在这里，我们研究了这种转变背后的机制。我们发现层粘连蛋白聚合通过基质金属蛋白酶 11 (Mmp11) 依赖性机制间接促进 MTJ 处的 Fn 下调。 Mmp11 定位到 MTJ 需要层粘连蛋白沉积和组织，其中 Mmp11 对于体内 Fn 下调既是必要的又是充分的。此外，层粘连蛋白突变体中残留 Mmp11 的减少会促进富含 Fn 的 MTJ，从而部分挽救骨骼肌结构。这些结果确定了 MTJ 处 Fn 下调的机制，突出了层粘连蛋白和 Fn 之间的串扰，并确定了 Mmp11 的新体内功能。综上所述，我们的数据证明了一种介导 Fn 下调的新信号通路。我们的数据揭示了体内形态发生过程中指导 ECM 重塑的新调控机制，可能会提示 Fn 失调的病理状况。
Remodeling of the extracellular matrix (ECM) regulates cell adhesion as well as signaling between cells and their microenvironment. Despite the importance of tightly regulated ECM remodeling for normal muscle development and function, mechanisms underlying ECM remodeling in vivo remain elusive. One excellent paradigm in which to study ECM remodeling in vivo is morphogenesis of the myotendinous junction (MTJ) during zebrafish skeletal muscle development. During MTJ development, there are dramatic shifts in the primary components comprising the MTJ matrix. One such shift involves the replacement of Fibronectin (Fn)-rich matrix, which is essential for both somite and early muscle development, with laminin-rich matrix essential for normal function of the myotome. Here, we investigate the mechanism underlying this transition. We show that laminin polymerization indirectly promotes Fn downregulation at the MTJ, via a matrix metalloproteinase 11 (Mmp11)-dependent mechanism. Laminin deposition and organization is required for localization of Mmp11 to the MTJ, where Mmp11 is both necessary and sufficient for Fn downregulation in vivo. Furthermore, reduction of residual Mmp11 in laminin mutants promotes a Fn-rich MTJ that partially rescues skeletal muscle architecture. These results identify a mechanism for Fn downregulation at the MTJ, highlight crosstalk between laminin and Fn, and identify a new in vivo function for Mmp11. Taken together, our data demonstrate a novel signaling pathway mediating Fn downregulation. Our data revealing new regulatory mechanisms that guide ECM remodeling during morphogenesis in vivo may inform pathological conditions in which Fn is dysregulated.