Synthetic lateral inhibition governs cell-type bifurcation with robust ratios
Synthetic lateral inhibition governs cell-type bifurcation with robust ratios
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DOI：
10.1038/ncomms7195
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发表时间：
2015-02-01
影响因子：
16.6
通讯作者：
Ebisuya, Miki
中科院分区：
文献类型：
--
作者：
Matsuda, Mitsuhiro;Koga, Makito;Ebisuya, Miki
多细胞生物的细胞类型多样性是通过一系列二元细胞命运决定创建的。由Delta-Notch信号控制控制的侧向抑制是通过均匀的相邻细胞选择替代细胞类型的核心机制。在这里，我们表明，用Delta-Notch依赖性的侧向抑制回路自发分叉成三角阳性和缺口活性细胞群体进行设计的细胞。合成的横向抑制作用包括对Delta的转录抑制和疯子边缘（LFNG）的细胞内反馈。 LFNG反馈子电路，即使单独的，也会引起自动细胞类型分叉。此外，通过横向抑制分叉的两个细胞群的比率可再现且可靠地抵抗扰动。细胞类型的比率可通过横向抑制回路的结构以及细胞 - 细胞附着程度可调节。因此，相邻细胞之间的最小横向抑制机制不仅是单个细胞的二元细胞类型转换，而且还控制细胞构型水平的细胞型比。
Cell-type diversity in multicellular organisms is created through a series of binary cell fate decisions. Lateral inhibition controlled by Delta-Notch signalling is the core mechanism for the choice of alternative cell types by homogeneous neighbouring cells. Here, we show that cells engineered with a Delta-Notch-dependent lateral inhibition circuit spontaneously bifurcate into Delta-positive and Notch-active cell populations. The synthetic lateral inhibition circuit comprises transcriptional repression of Delta and intracellular feedback of Lunatic fringe (Lfng). The Lfng-feedback subcircuit, even alone, causes the autonomous cell-type bifurcation. Furthermore, the ratio of two cell populations bifurcated by lateral inhibition is reproducible and robust against perturbation. The cell-type ratio is adjustable by the architecture of the lateral inhibition circuit as well as the degree of cell-cell attachment. Thus, the minimum lateral inhibition mechanism between adjacent cells not only serves as a binary cell-type switch of individual cells but also governs the cell-type ratio at the cell-population level.