Roy Nicole M, Sagerström Charles G
Department of Biochemistry and Molecular Pharmacology, and Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street-LRB 822, Worcester, MA 01605, USA.
Brain Res Dev Brain Res. 2004 Jan 31;148(1):27-42. doi: 10.1016/j.devbrainres.2003.10.005.
We have explored the role of fibroblast growth factor (Fgf) signaling in regulating gene expression in the early zebrafish hindbrain primordium. We demonstrate that a dominant negative Fgf receptor (FgfR) construct disrupts gene expression along the entire rostrocaudal axis of the hindbrain primordium and, using an FgfR antagonist, we find that this Fgf signal is required at early gastrula stages. This effect cannot be mimicked by morpholino antisense oligos to Fgf3, Fgf8 or Fgf24--three Fgf family members known to be secreted from signaling centers at the midbrain-hindbrain boundary (MHB), in rhombomere 4 and in caudal mesoderm at gastrula stages. We propose that an Fgf signal is required in the early gastrula to initiate hindbrain gene expression and that this is distinct from the later roles of Fgfs in patterning the hindbrain during late gastrula/early segmentation stages. We also find that blocking either retinoic acid (RA) or Fgf signaling disrupts hindbrain gene expression at gastrula stages, suggesting that both pathways are essential at this stage. However, both pathways must be blocked simultaneously to disrupt hindbrain gene expression at segmentation stages, indicating that these signaling pathways become redundant at later stages. Furthermore, exogenous application of RA or Fgf alone is sufficient to induce hindbrain genes in gastrula stage tissues, suggesting that the two-signal requirement can be overcome under some conditions. Our results demonstrate an early role for Fgf signaling and reveal a dynamic relationship between the RA and Fgf signaling pathways during hindbrain development.
我们探究了成纤维细胞生长因子（Fgf）信号在调控斑马鱼早期后脑原基基因表达中的作用。我们证明，一种显性负性Fgf受体（FgfR）构建体可破坏后脑原基沿整个前后轴的基因表达，并且使用FgfR拮抗剂，我们发现这种Fgf信号在原肠胚早期阶段是必需的。这种效应不能被针对Fgf3、Fgf8或Fgf24的吗啉代反义寡核苷酸模拟——这三个Fgf家族成员已知在原肠胚阶段从中脑-后脑边界（MHB）、菱脑节4以及尾侧中胚层的信号中心分泌。我们提出，在原肠胚早期需要一种Fgf信号来启动后脑基因表达，并且这与Fgfs在原肠胚后期/早期体节形成阶段对后脑进行模式化的后期作用不同。我们还发现，阻断视黄酸（RA）或Fgf信号都会破坏原肠胚阶段的后脑基因表达，这表明这两条通路在这个阶段都是必不可少的。然而，必须同时阻断这两条通路才能破坏体节形成阶段的后脑基因表达，这表明这些信号通路在后期变得冗余。此外，单独外源性应用RA或Fgf足以在原肠胚阶段组织中诱导后脑基因，这表明在某些条件下可以克服对两种信号的需求。我们的结果证明了Fgf信号的早期作用，并揭示了后脑发育过程中RA和Fgf信号通路之间的动态关系。
