Vinothkumar Saradavey, Rastegar Sepand, Takamiya Masanari, Ertzer Raymond, Strähle Uwe
Institute for Toxicology and Genetics, Forschungszentrum Karlsruhe, Postfach 3640, 76021 Karlsruhe, Germany.
Dev Biol. 2008 Feb 1;314(1):200-14. doi: 10.1016/j.ydbio.2007.11.034. Epub 2007 Dec 7.
The signaling molecule Sonic hedgehog (Shh) is required for differentiation of the vertebrate retina. In the developing zebrafish retina, shh expression is initiated at the ventronasal region, from where it spreads as a wave through the retina. To investigate the molecular mechanism underlying this coordinated expression of shh, we mapped the cis-regulatory region and identified a novel regulatory sequence in the first intron of the shh locus. This sequence contains binding sites for the transcription factors Erm and Pea3 that are known transducers of Fgf signaling. Mutation of the binding sites or knockdown of Pea3 and Erm abolishes transgene expression, indicating that Fgf signaling regulates shh expression in the retina. We provide evidence that Fgf3 and -8 control initiation of expression, while Fgf19 is crucial for the propagation of transgene expression through the retina. Inhibitor experiments indicate a continued requirement of FGF and Hedgehog (Hh) signaling for transgene expression after initiation at the ventronasal aspect of the retina. We propose a model, in which Fgf3 and -8 initiate expression and Fgf19 and Shh signals cooperate subsequently to promote establishment of expression throughout the retina.
信号分子音猬因子（Shh）是脊椎动物视网膜分化所必需的。在发育中的斑马鱼视网膜中，shh表达始于鼻腹侧区域，并从该区域以波的形式扩散至整个视网膜。为了研究shh这种协调表达背后的分子机制，我们绘制了顺式调控区域图谱，并在shh基因座的第一个内含子中鉴定出一个新的调控序列。该序列包含转录因子Erm和Pea3的结合位点，而这两种转录因子是已知的Fgf信号转导分子。结合位点的突变或Pea3和Erm的敲低会消除转基因表达，这表明Fgf信号调节视网膜中的shh表达。我们提供的证据表明，Fgf3和Fgf8控制表达的起始，而Fgf19对于转基因表达在整个视网膜中的传播至关重要。抑制剂实验表明，在视网膜鼻腹侧起始后，转基因表达持续需要FGF和刺猬因子（Hh）信号。我们提出了一个模型，其中Fgf3和Fgf8启动表达，随后Fgf19和Shh信号协同作用以促进整个视网膜表达的建立。
