Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro
Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro
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DOI：
10.1091/mbc.e09-06-0491
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发表时间：
2009-12-01
影响因子：
3.3
通讯作者：
Krauss, Robert S.
中科院分区：
文献类型：
--
作者：
Bae, Gyu-Un;Yang, Youn-Joo;Krauss, Robert S.
多种信号通路参与骨骼肌的发育，但在肌纤维形成中调节这些通路的细胞外信号尚不清楚。再生蛋白是参与轴突导向的netrin和排斥导向分子（RGM）家族的配体的受体。我们以前报道，再生素促进肌管形成的C2 C12成肌细胞在体外和相关蛋白Cdo（也Cdon）是一个潜在的再生素辅助受体成肌细胞。我们在这里报告，小鼠纯合子的基因陷阱突变的Neo 1基因座（编码再生蛋白）正常发育肌节，但有小肌纤维在胚胎第18.5天，在3周龄。类似地，与来自对照动物的成肌细胞相比，来自这些动物的培养的成肌细胞形成具有更少核的更小的肌管。这些体内和体外缺陷与低水平的活化形式的粘着斑激酶（FAK）和细胞外信号调节激酶（ERK）相关，这两种激酶已知参与肌管形成，以及某些肌肉特异性蛋白质的低效表达。重组netrin-2激活FAK和ERK在培养的成肌细胞在再生蛋白和Cdo依赖性的方式，而重组RGMc显示较低的能力，激活这些激酶。总之，netrin-neogenin信号传导是调节肌原分化和肌纤维大小的重要细胞外线索。
A variety of signaling pathways participate in the development of skeletal muscle, but the extracellular cues that regulate such pathways in myofiber formation are not well understood. Neogenin is a receptor for ligands of the netrin and repulsive guidance molecule (RGM) families involved in axon guidance. We reported previously that neogenin promoted myotube formation by C2C12 myoblasts in vitro and that the related protein Cdo (also Cdon) was a potential neogenin coreceptor in myoblasts. We report here that mice homozygous for a gene-trap mutation in the Neo1 locus (encoding neogenin) develop myotomes normally but have small myofibers at embryonic day 18.5 and at 3 wk of age. Similarly, cultured myoblasts derived from such animals form smaller myotubes with fewer nuclei than myoblasts from control animals. These in vivo and in vitro defects are associated with low levels of the activated forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), both known to be involved in myotube formation, and inefficient expression of certain muscle-specific proteins. Recombinant netrin-2 activates FAK and ERK in cultured myoblasts in a neogenin-and Cdo-dependent manner, whereas recombinant RGMc displays lesser ability to activate these kinases. Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size.