Nrk2b-mediated NAD plus production regulates cell adhesion and is required for muscle morphogenesis in vivo Nrk2b and NAD+ in muscle morphogenesis
Nrk2b-mediated NAD plus production regulates cell adhesion and is required for muscle morphogenesis in vivo Nrk2b and NAD+ in muscle morphogenesis
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DOI：
10.1016/j.ydbio.2010.05.513
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发表时间：
2010-08-15
影响因子：
2.7
通讯作者：
Henry, Clarissa A.
中科院分区：
文献类型：
--
作者：
Goody, Michelle F.;Kelly, Meghan W.;Henry, Clarissa A.
细胞-基质粘附复合物（CMAC）在形态发生过程中起着重要作用。鉴于CMAC的普遍存在的性质及其在许多细胞过程中的作用，一个问题是如何调节CMAC功能的特异性。明确定义的细胞行为，产生节段重复轴向骨骼肌在斑马鱼的发展过程中，包括一个理想的系统，调查CMAC功能在形态发生。我们发现烟酰胺核苷激酶2b（Nrk 2b）细胞在体内自主调节CMAC的分子组成。Nrk 2b是肌腱连接处（MTJ）正常层粘连蛋白聚合所必需的。在Nrk 2b缺陷的胚胎中，在层粘连蛋白没有正确聚合的MTJ位点，肌纤维伸长到相邻的肌节中并且异常长。在酵母和人类细胞中，Nrk 2磷酸化烟酰胺核苷并通过替代补救途径产生NAD+。外源性NAD+处理挽救了Nrk 2b缺陷胚胎中的MTJ发育，但不在层粘连蛋白突变胚胎中。Nrk 2b和层粘连蛋白都是桩蛋白定位于MTJ处的CMAC所必需的，但不是β-肌营养不良聚糖。在Nrk 2b缺陷胚胎中过表达桩蛋白足以挽救MTJ完整性。总之，这些数据表明，Nrk 2b在调节离散CMAC组分的亚细胞定位中起着特定的作用，而离散CMAC组分又在肌肉骨骼发育中起着作用。此外，这些数据表明，Nrk 2b介导的NAD+的合成在功能上是MTJ发育期间层粘连蛋白粘附和桩蛋白亚细胞定位的上游。这些结果表明，以前未认识到的复杂性，CMAC组装在体内，也阐明了一个新的作用，NAD+在形态发生。(C)2010年爱思唯尔公司All rights reserved.
Cell-matrix adhesion complexes (CMACs) play fundamental roles during morphogenesis. Given the ubiquitous nature of CMACs and their roles in many cellular processes, one question is how specificity of CMAC function is modulated. The clearly defined cell behaviors that generate segmentally reiterated axial skeletal muscle during zebrafish development comprise an ideal system with which to investigate CMAC function during morphogenesis. We found that Nicotinamide riboside kinase 2b (Nrk2b) cell autonomously modulates the molecular composition of CMACs in vivo. Nrk2b is required for normal Laminin polymerization at the myotendinous junction (MTJ). In Nrk2b-deficient embryos, at MTJ loci where Laminin is not properly polymerized, muscle fibers elongate into adjacent myotomes and are abnormally long. In yeast and human cells, Nrk2 phosphorylates Nicotinamide Riboside and generates NAD+ through an alternative salvage pathway. Exogenous NAD+ treatment rescues MTJ development in Nrk2b-deficient embryos, but not in laminin mutant embryos. Both Nrk2b and Laminin are required for localization of Paxillin, but not beta-Dystroglycan, to CMACs at the MTJ. Overexpression of Paxillin in Nrk2b-deficient embryos is sufficient to rescue MTJ integrity. Taken together, these data show that Nrk2b plays a specific role in modulating subcellular localization of discrete CMAC components that in turn plays roles in musculoskeletal development. Furthermore, these data suggest that Nrk2b-mediated synthesis of NAD+ is functionally upstream of Laminin adhesion and Paxillin subcellular localization during MTJ development. These results indicate a previously unrecognized complexity to CMAC assembly in vivo and also elucidate a novel role for NAD+ during morphogenesis. (C) 2010 Elsevier Inc. All rights reserved.