Cohen Michael, Kicheva Anna, Ribeiro Ana, Blassberg Robert, Page Karen M, Barnes Chris P, Briscoe James
MRC-National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Department of Mathematics and CoMPLEX, University College London, Gower Street, London WC1E 6BT, UK.
Nat Commun. 2015 Apr 2;6:6709. doi: 10.1038/ncomms7709.
In the vertebrate neural tube, the morphogen Sonic Hedgehog (Shh) establishes a characteristic pattern of gene expression. Here we quantify the Shh gradient in the developing mouse neural tube and show that while the amplitude of the gradient increases over time, the activity of the pathway transcriptional effectors, Gli proteins, initially increases but later decreases. Computational analysis of the pathway suggests three mechanisms that could contribute to this adaptation: transcriptional upregulation of the inhibitory receptor Ptch1, transcriptional downregulation of Gli and the differential stability of active and inactive Gli isoforms. Consistent with this, Gli2 protein expression is downregulated during neural tube patterning and adaptation continues when the pathway is stimulated downstream of Ptch1. Moreover, the Shh-induced upregulation of Gli2 transcription prevents Gli activity levels from adapting in a different cell type, NIH3T3 fibroblasts, despite the upregulation of Ptch1. Multiple mechanisms therefore contribute to the intracellular dynamics of Shh signalling, resulting in different signalling dynamics in different cell types.
在脊椎动物神经管中，形态发生素音猬因子（Shh）建立了一种特征性的基因表达模式。在此，我们对发育中的小鼠神经管内的Shh梯度进行了量化，并表明虽然梯度幅度随时间增加，但该信号通路转录效应因子Gli蛋白的活性最初增加，随后降低。对该信号通路的计算分析表明，有三种机制可能导致这种适应性变化：抑制性受体Ptch1的转录上调、Gli的转录下调以及活性和非活性Gli亚型的稳定性差异。与此一致的是，在神经管模式形成过程中Gli2蛋白表达下调，并且当该信号通路在Ptch1下游受到刺激时，适应性变化仍会持续。此外，尽管Ptch1上调，但Shh诱导的Gli2转录上调阻止了Gli活性水平在另一种细胞类型NIH3T3成纤维细胞中发生适应性变化。因此，多种机制共同作用于Shh信号的细胞内动态变化，导致不同细胞类型中出现不同的信号动态。
