Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis.
Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis.
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DOI：
10.1101/gad.270785.115
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发表时间：
2016-01-01
影响因子：
10.5
通讯作者：
Kageyama R
中科院分区：
文献类型：
--
作者：
Shimojo H;Isomura A;Ohtsuka T;Kori H;Miyachi H;Kageyama R
Shimojo等人开发了一种实时成像系统，发现Notch配体Delta-like 1（Dll 1）蛋白表达在神经祖细胞和前体中胚层细胞中振荡，这调节了动态基因表达和组织形态发生。Notch信号通过细胞-细胞相互作用调节组织形态发生。Notch效应子Hes 1和Hes 7以振荡方式表达，并分别调节发育过程，如神经发生和体节发生。小鼠Notch配体Delta样1（Dll 1）的mRNA表达也是振荡的。然而，Dll 1蛋白表达的动态是有争议的，其功能意义是未知的。在这里，我们开发了一个实时成像系统，发现Dll 1蛋白表达在神经祖细胞和前体中胚层细胞中振荡。值得注意的是，当通过缩短或延长Dll 1基因来加速或延迟Dll 1表达时，Dll 1振荡在中间水平变得严重抑制或淬灭，如数学模型所示。在此条件下，Hes 1和Hes 7振荡也被抑制。在前体节中胚层，稳定的Dll 1表达导致体节及其衍生物，如椎骨和肋骨严重融合。在发育中的脑中，稳定的Dll 1表达抑制神经祖细胞的增殖并加速神经发生，而Dll 1振荡的光遗传诱导有效地维持神经祖细胞。这些结果表明，Dll 1表达的适当时机是至关重要的振荡网络，并建议振荡细胞-细胞相互作用在组织形态发生的功能意义。
Shimojo et al. developed a live-imaging system and found that Notch ligand Delta-like1 (Dll1) protein expression oscillates in neural progenitors and presomitic mesoderm cells, and this regulates dynamic gene expression and tissue morphogenesis. Notch signaling regulates tissue morphogenesis through cell–cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell–cell interactions in tissue morphogenesis.