Müller F, Albert S, Blader P, Fischer N, Hallonet M, Strähle U
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, CU de Strasbourg, France.
Development. 2000 Sep;127(18):3889-97. doi: 10.1242/dev.127.18.3889.
The secreted molecule Sonic hedgehog (Shh) is crucial for floor plate and ventral brain development in amniote embryos. In zebrafish, mutations in cyclops (cyc), a gene that encodes a distinct signal related to the TGF(beta) family member Nodal, result in neural tube defects similar to those of shh null mice. cyc mutant embryos display cyclopia and lack floor plate and ventral brain regions, suggesting a role for Cyc in specification of these structures. cyc mutants express shh in the notochord but lack expression of shh in the ventral brain. Here we show that Cyc signalling can act directly on shh expression in neural tissue. Modulation of the Cyc signalling pathway by constitutive activation or inhibition of Smad2 leads to altered shh expression in zebrafish embryos. Ectopic activation of the shh promoter occurs in response to expression of Cyc signal transducers in the chick neural tube. Furthermore an enhancer of the shh gene, which controls ventral neural tube expression, is responsive to Cyc signal transducers. Our data imply that the Nodal related signal Cyc induces shh expression in the ventral neural tube. Based on the differential responsiveness of shh and other neural tube specific genes to Hedgehog and Cyc signalling, a two-step model for the establishment of the ventral midline of the CNS is proposed.
分泌分子音猬因子（Shh）对于羊膜动物胚胎的底板和腹侧脑发育至关重要。在斑马鱼中，独眼畸形（cyc）基因发生突变，该基因编码一种与转化生长因子β（TGF-β）家族成员Nodal相关的独特信号，会导致类似于Shh基因敲除小鼠的神经管缺陷。cyc突变体胚胎表现出独眼畸形，且缺乏底板和腹侧脑区域，这表明Cyc在这些结构的特化中发挥作用。cyc突变体在脊索中表达Shh，但在腹侧脑中缺乏Shh表达。在此我们表明，Cyc信号可直接作用于神经组织中Shh的表达。通过组成型激活或抑制Smad2来调节Cyc信号通路，会导致斑马鱼胚胎中Shh表达发生改变。在鸡神经管中，Cyc信号转导子的表达会引发Shh启动子的异位激活。此外，控制腹侧神经管表达的Shh基因增强子对Cyc信号转导子有反应。我们的数据表明，与Nodal相关的信号Cyc诱导腹侧神经管中Shh的表达。基于Shh和其他神经管特异性基因对刺猬因子和Cyc信号的不同反应性，提出了一个建立中枢神经系统腹侧中线的两步模型。
