Competition in Notch Signaling with Cis Enriches Cell Fate Decisions

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.Notch信号通路（Notch signaling）参与后生动物（Metazoa）胚胎发育过程中的细胞命运抉择。通常而言，Notch信号通路源于相邻细胞表面Notch受体与其配体的结合，以此介导细胞间通讯。然而，学界已证实，Notch信号通路亦可通过配体依赖性与配体非依赖性两种机制实现细胞自主性调控。此类案例包括无需配体结合即可激活的Notch信号，以及单个细胞内配体与Notch受体结合引发的受体滴定效应，从而实现的Notch通路顺式抑制（cis-inhibition）。越来越多的实验证据表明，细胞内Notch受体与其配体的结合（顺式相互作用，cis-interactions）同样可触发细胞自主性的Notch信号（顺式信号，cis-signaling），但其对细胞命运决定与模式形成的潜在效应仍有待深入探究。 为解答这一科学问题，本文从数学与计算层面，探究了顺式信号与其他Notch信号来源（包括细胞自主性信号或依赖细胞间通讯的信号）共同作用下产生的细胞状态。 本研究发现，顺式信号可从驱动顺式激活（cis-activation）转向有效发挥顺式抑制作用，并明确了该转换发生的条件。该转换源于不同信号来源间的竞争——这些信号共享同一受体，但信号转导效率存在差异。 我们提出，顺式相互作用及其介导的信号在精细模式形成与细胞命运决定中的作用，取决于其介导的是顺式激活还是顺式抑制，而这一过程可在发育过程中被调控。具体而言，顺式抑制而非顺式激活可促进模式形成，并通过以下方式丰富模式样态：调节高配体表达状态的细胞比例、生成条纹等额外周期性模式，以及实现对前体状态高度敏感的局域模式形成与细胞自主性双稳态（bistability）。 本研究揭示了多信号来源共享同一受体时调控机制的复杂性，并为其特征解析提供了研究工具。