Error Minimization in Lateral Inhibition Circuits
Error Minimization in Lateral Inhibition Circuits
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DOI：
10.1126/scisignal.2000857
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发表时间：
2010-07-06
影响因子：
7.3
通讯作者：
Barkai, Naama
中科院分区：
文献类型：
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作者：
Barad, Omer;Rosin, Dalia;Barkai, Naama
果蝇感觉刚毛的模式具有显著的可重复性。每根刚毛起源于一个感觉器官前体细胞（SOP），该细胞是通过侧抑制过程从一群前体细胞中选择出来的。虽然这一过程的特征很好，但确保其稳健性的机制仍然不清楚。使用概率模型，我们定义了SOP选择中的错误来源，并检查了它们如何依赖于潜在的分子电路。我们发现，快速抑制非选择细胞的神经分化，再加上选择时间的细胞间高度可变性，对于准确的SOP选择至关重要。Notch受体与其配体Delta或Serrate之间的细胞自主相互作用（顺式相互作用）通过缩短抑制信号在一个细胞内启动与作用于邻近细胞的时间之间的有效延迟，促进了准确的SOP选择，这表明选择依赖于Notch与其配体的顺式和反式相互作用之间的竞争。顺式相互作用模型预测，随着Notch丰度的降低，异位SOP选择的增加可以通过减少Notch配体Delta和Serrate的丰度来补偿。我们通过实验验证了这一预测，量化了携带Notch、Delta或Serrate等位基因杂合零突变或这些等位基因组合的果蝇异位鬃毛的频率。我们提出，对错误的易感性区分了调节图案形成的发育回路的看似相同的设计。
The pattern of the sensory bristles in the fruit fly Drosophila is remarkably reproducible. Each bristle arises from a sensory organ precursor (SOP) cell that is selected, through a lateral inhibition process, from a cluster of proneural cells. Although this process is well characterized, the mechanism ensuring its robustness remains obscure. Using probabilistic modeling, we defined the sources of error in SOP selection and examined how they depend on the underlying molecular circuit. We found that rapid inhibition of the neural differentiation of nonselected cells, coupled with high cell-to-cell variability in the timing of selection, is crucial for accurate SOP selection. Cell-autonomous interactions (cis interactions) between the Notch receptor and its ligands Delta or Serrate facilitate accurate SOP selection by shortening the effective delay between the time when the inhibitory signal is initiated in one cell and the time when it acts on neighboring cells, suggesting that selection relies on competition between cis and trans interactions of Notch with its ligands. The cis interaction model predicts that the increase in ectopic SOP selections observed with reduced Notch abundance can be compensated for by reducing the abundance of the Notch ligands Delta and Serrate. We validated this prediction experimentally by quantifying the frequency of ectopic bristles in flies carrying heterozygous null mutations of Notch, Delta, or Serrate or combinations of these alleles. We propose that susceptibility to errors distinguishes seemingly equivalent designs of developmental circuits regulating pattern formation.