Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here, we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of synNotch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests that the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

中文翻译：

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接触区域和组织生长动力学塑造合成的 juxtacrine 信号传导模式


通过直接接触或近位信号传导进行的细胞间通讯在发育、疾病和生理学的许多领域都很重要。合成形式的 juxtacrine 信号转导可以被精确控制并与天然过程正交运行，使其成为解决体内细胞间通讯中基本问题的强大还原工具。在这里，我们通过在果蝇翅膀假想盘中实施定制的合成基因电路以及数学建模来确定合成 Notch （synNotch） 激活模式，研究细胞间接触长度和组织生长动力学如何影响 juxtacrine 信号反应。我们发现细胞之间的接触面积在很大程度上决定了 synNotch 激活的程度，从而预测信号发送和信号接收细胞之间界面的形状将影响 synNotch 响应的大小。值得注意的是，synNotch 输出形成一个渐变的空间图谱，从信号源延伸了几个细胞直径，提供了证据，证明对 juxtacrine 信号的反应可以在细胞中持续存在，因为它们从源细胞增殖出去，或者细胞仍然能够在几个细胞直径上直接通信。我们的模型表明，前一种机制可能就足够了，因为它预测了没有扩散或长距离细胞间通信的分级输出。总体而言，我们确定细胞间接触面积以及输出合成和衰变速率可能控制组织生长过程中 synNotch 输出在空间和时间上的模式，这些见解可能对一般的 juxtacrine 信号传导具有更广泛的影响。