Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Dev Biol. 2012 Nov 15;371(2):235-45. doi: 10.1016/j.ydbio.2012.08.017. Epub 2012 Aug 30.
Fibroblast growth factor (FGF) signaling has been shown to play critical roles in vertebrate segmentation and elongation of the embryonic axis. Neither the exact roles of FGF signaling, nor the identity of the FGF ligands involved in these processes, has been conclusively determined. Fgf8 is required for cell migration away from the primitive streak when gastrulation initiates, but previous studies have shown that drastically reducing the level of FGF8 later in gastrulation has no apparent effect on somitogenesis or elongation of the embryo. In this study, we demonstrate that loss of both Fgf8 and Fgf4 expression during late gastrulation resulted in a dramatic skeletal phenotype. Thoracic vertebrae and ribs had abnormal morphology, lumbar and sacral vertebrae were malformed or completely absent, and no tail vertebrae were present. The expression of Wnt3a in the tail and the amount of nascent mesoderm expressing Brachyury were both severely reduced. Expression of genes in the NOTCH signaling pathway involved in segmentation was significantly affected, and somite formation ceased after the production of about 15-20 somites. Defects seen in the mutants appear to result from a failure to produce sufficient paraxial mesoderm, rather than a failure of mesoderm precursors to migrate away from the primitive streak. Although the epiblast prematurely decreases in size, we did not detect evidence of a change in the proliferation rate of cells in the tail region or excessive apoptosis of epiblast or mesoderm cells. We propose that FGF4 and FGF8 are required to maintain a population of progenitor cells in the epiblast that generates mesoderm and contributes to the stem cell population that is incorporated in the tailbud and required for axial elongation of the mouse embryo after gastrulation.
成纤维细胞生长因子（FGF）信号已被证明在脊椎动物分节和胚胎轴的伸长中发挥关键作用。FGF 信号的确切作用，以及参与这些过程的 FGF 配体的身份，尚未得到明确确定。当原肠胚发生开始时，Fgf8 对于细胞从原始条纹向外迁移是必需的，但是先前的研究表明，在原肠胚发生后期大大降低 FGF8 的水平对体节形成或胚胎伸长没有明显影响。在这项研究中，我们证明了晚期原肠胚发生期间 Fgf8 和 Fgf4 表达的丧失导致了明显的骨骼表型。胸椎体和肋骨形态异常，腰椎和骶骨椎体畸形或完全缺失，没有尾椎体。尾巴中的 Wnt3a 表达和表达 Brachyury 的新生中胚层的数量都严重减少。参与分节的 NOTCH 信号通路中的基因表达受到显著影响，并且在产生约 15-20 个体节后体节形成停止。突变体中观察到的缺陷似乎是由于未能产生足够的轴旁中胚层，而不是中胚层前体未能从原始条纹向外迁移。尽管外胚层的大小会过早减小，但我们没有检测到尾部区域细胞增殖率发生变化的证据，也没有检测到外胚层或中胚层细胞过度凋亡的证据。我们提出，FGF4 和 FGF8 对于维持外胚层中的祖细胞群体是必需的，该群体产生中胚层并有助于纳入尾芽的干细胞群体，并为原肠胚发生后小鼠胚胎的轴向伸长提供必需的。
