Competition in notch signaling with cis enriches cell fate decisions.
Competition in notch signaling with cis enriches cell fate decisions.
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DOI：
10.1371/journal.pone.0095744
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ibañes M
中科院分区：
文献类型：
--
作者：
Formosa-Jordan P;Ibañes M
Notch信号参与后生动物胚胎发育过程中细胞命运的选择。通常，Notch信号产生于Notch受体与相邻细胞中的配体结合，驱动细胞间的通讯。然而，通过配体依赖性和配体非依赖性机制对Notch信号的细胞自主控制也是已知的。例子包括在没有配体结合的情况下产生的Notch信号，以及通过在单个细胞内与配体结合时滴定Notch受体来顺式抑制Notch信号。越来越多的实验证据支持Notch受体与其配体在细胞内的结合（顺式相互作用）也可以触发细胞自主的Notch信号（顺式信号），其对细胞命运决定和模式的潜在影响仍然知之甚少。为了解决这个问题，本文用数学和计算的方法研究了顺式信号与额外的Notch信号源结合产生的细胞状态，这些信号源要么是细胞自主的，要么涉及细胞间的通信。我们的研究表明，顺式信号传导可以从驱动顺式激活转变为有效地执行顺式抑制，并确定在何种条件下发生这种转变。这种转换依赖于Notch信号来源之间的竞争，它们共享相同的受体，但信号效率不同。我们提出顺式相互作用及其信号在细粒度模式和细胞命运决定中的作用取决于它们是否驱动顺式抑制或顺式激活，这可以在发育过程中控制。具体来说，顺式抑制和非顺式激活通过调节高配体表达状态的细胞比例，通过启用额外的周期性模式（如条纹），以及通过允许对前体状态和细胞自主双稳定性高度敏感的局部模式，促进了模式的形成并丰富了模式。我们的研究举例说明了当多个信号来源共享相同的受体时，调控的复杂性，并为其表征提供了工具。
Notch signaling is involved in cell fate choices during the embryonic development of Metazoa. Commonly, Notch signaling arises from the binding of the Notch receptor to its ligands in adjacent cells driving cell-to-cell communication. Yet, cell-autonomous control of Notch signaling through both ligand-dependent and ligand-independent mechanisms is known to occur as well. Examples include Notch signaling arising in the absence of ligand binding, and cis-inhibition of Notch signaling by titration of the Notch receptor upon binding to its ligands within a single cell. Increasing experimental evidences support that the binding of the Notch receptor with its ligands within a cell (cis-interactions) can also trigger a cell-autonomous Notch signal (cis-signaling), whose potential effects on cell fate decisions and patterning remain poorly understood. To address this question, herein we mathematically and computationally investigate the cell states arising from the combination of cis-signaling with additional Notch signaling sources, which are either cell-autonomous or involve cell-to-cell communication. Our study shows that cis-signaling can switch from driving cis-activation to effectively perform cis-inhibition and identifies under which conditions this switch occurs. This switch relies on the competition between Notch signaling sources, which share the same receptor but differ in their signaling efficiency. We propose that the role of cis-interactions and their signaling on fine-grained patterning and cell fate decisions is dependent on whether they drive cis-inhibition or cis-activation, which could be controlled during development. Specifically, cis-inhibition and not cis-activation facilitates patterning and enriches it by modulating the ratio of cells in the high-ligand expression state, by enabling additional periodic patterns like stripes and by allowing localized patterning highly sensitive to the precursor state and cell-autonomous bistability. Our study exemplifies the complexity of regulations when multiple signaling sources share the same receptor and provides the tools for their characterization.
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