Self-organization for sensory brushes Sensory hairs on the back of a fruit fly are lined up in neat rows. The orderliness of this arrangement has encouraged models based on organized specification of the hairs. Corson et al. now show that development is both less precise and more effective than that. They used mathematical modeling to recapitulate genetic effects as the developing epidermis becomes organized into enough rows and single lines of hairs. Their work suggests that the sensory field develops through self-organizing patterning that can adjust to the size of the epidermis. Science, this issue p. eaai7407 Distributed and flexible patterning combines with cell-cell interactions to establish rows of sensory bristles on the fly thorax. INTRODUCTION Spatial patterning in developing multicellular organisms relies on positional cues and cell-cell interactions. Stereotyped sensory organ arrangements in Drosophila are commonly attributed to a prepattern that defines regions of neural competence. Notch-mediated interactions then isolate sensory organ precursor (SOP) cells from among the competent cells. In support of this view, prepattern factors direct the expression of proneural factors in discrete clusters and determine the location of large bristles on the dorsal thorax. However, no such prepattern is known to establish the proneural stripes that give rise to finer-bristle rows. RATIONALE By analogy with reaction-diffusion systems, we wondered whether Notch-mediated cell-cell interactions might organize a pattern of proneural stripes. To explore a possible role for Notch in proneural patterning, we generated fluorescent reporters for the proneural factors Achaete and Scute, the ligand Delta, and the Notch early-response factor E(spl)m3-HLH, which antagonizes proneural activity. We observed expression of these reporters in live and fixed samples throughout early pupal development. In parallel, we developed a mathematical model for Notch-mediated patterning. In this abstract model, the dynamics of a cell is expressed in terms of just two variables, for the state of the cell and the level of signal it receives. The model incorporates a series of plausible assumptions that govern its patterning behavior: Cells, which adopt the SOP fate in the absence of signal and the alternative, epidermal fate under high enough signal, exhibit a bistable response under intermediate signal levels. Inhibitory signaling from a cell varies nonlinearly with cell state and reaches beyond immediate neighbors. RESULTS Before the onset of proneural gene expression, a bimodal gradient of Delta expression drove Notch activity; as a result of cis-inhibition, Notch was activated only in regions of intermediate Delta levels. This defined an inhibitory template for a first series of three proneural stripes. The spatial pattern of Notch activity dynamically changed as these first proneural stripes emerged, forming a negative template for a second group of intercalating stripes. Eventually, each stripe resolved into a row of isolated SOPs through Notch signaling. Thus, Notch mediated both proneural stripe patterning and SOP selection via a self-organized process. Simulations of the model, with a time-dependent inhibitory gradient describing the proneural-independent signaling seen in vivo, recapitulated the sequential emergence and resolution of proneural stripes. In both model and experiments, mutual inhibition drove a gradual refinement of the proneural group, concomitant with the buildup of proneural activity. Cells on the sides of the stripes were excluded first, such that stripes narrowed before isolated SOPs emerged. In terms of the model, cell-intrinsic bistability allowed cells with higher proneural activity, at the center of the stripes, to evade levels of inhibition that were sufficient to exclude cells on the sides. Nonlinear signaling allowed a smooth transition from weak mutual inhibition within an extended proneural group to strong lateral inhibition from emerging SOPs, ensuring that attrition of the proneural group proceeds until only isolated cells remain. Finally, the model correctly predicted the outcome of perturbation experiments affecting the pattern of Notch activity, the level and activity of Delta, and the range of signaling. CONCLUSION Our results show that self-organized Notch signaling can establish stripe and dot patterns on a tissue-wide scale. A transient spatial bias, mediated by an initial gradient of Delta, is transduced by cell-cell interactions to produce a finer pattern of proneural stripes and bristle rows. Input from extrinsic positional cues and self-organization, sometimes considered competing paradigms for fate patterning, combine during bristle development and operate through the same signal. Self-organized Notch dynamics may provide a flexible substrate to generate diverse patterns in response to varying inputs. Self-organized bristle patterning. (Top) Input from a prepattern (green, Delta) and cell-cell interactions [red, Achaete; blue, Senseless; green, E(spl)m3-HLH] combine to establish a regular pattern of bristle rows on the Drosophila thorax. (Bottom) A mathematical model incorporating cell-intrinsic bistability (magenta, SOP; green, epidermis) recapitulates proneural stripe patterning and the singling out of SOPs (red and magenta, cell state; green, signal). The emergence of spatial patterns in developing multicellular organisms relies on positional cues and cell-cell communication. Drosophila sensory organs have informed a paradigm in which these operate in two distinct steps: Prepattern factors drive localized proneural activity, then Notch-mediated lateral inhibition singles out neural precursors. Here we show that self-organization through Notch signaling also establishes the proneural stripes that resolve into rows of sensory bristles on the fly thorax. Patterning, initiated by a gradient of Delta ligand expression, progresses through inhibitory signaling between and within stripes. Thus, Notch signaling can support self-organized tissue patterning as a prepattern is transduced by cell-cell interactions into a refined arrangement of cellular fates.

中文翻译：

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自组织 Notch 动力学在果蝇中产生刻板的感觉器官模式

感觉刷的自组织 果蝇背部的感觉毛排列整齐。这种排列的有序性鼓励了基于头发组织规范的模型。科森等人。现在表明，发展既不那么精确，也更有效。当发育中的表皮组织成足够多的行和单行毛发时，他们使用数学模型来概括遗传效应。他们的工作表明，感觉场是通过自组织模式发展起来的，这种模式可以适应表皮的大小。科学，这个问题 p。eaai7407 分布式和灵活的图案与细胞间相互作用相结合，在苍蝇胸部建立成排的感觉刷毛。介绍 发育中的多细胞生物的空间模式依赖于位置线索和细胞间相互作用。果蝇中刻板的感觉器官排列通常归因于定义神经能力区域的预模式。Notch 介导的相互作用然后从感受态细胞中分离出感觉器官前体 (SOP) 细胞。为支持这一观点，预模式因素指导原神经因素在离散簇中的表达，并确定背胸大刷毛的位置。然而，已知没有这样的预图案可以建立产生更细刷毛行的前神经条纹。基本原理通过与反应扩散系统类比，我们想知道 Notch 介导的细胞-细胞相互作用是否可能组织一种原神经条纹模式。为了探索 Notch 在原神经模式形成中的可能作用，我们为原神经因子 Achaete 和 Scute、配体 Delta 和 Notch 早期反应因子 E(spl)m3-HLH 生成了荧光报告基因，后者可对抗原神经活动。我们在整个早期蛹发育过程中观察到这些记者在活样本和固定样本中的表达。同时，我们为 Notch 介导的图案化开发了一个数学模型。在这个抽象模型中，细胞的动态仅用两个变量表示，分别是细胞的状态和它接收的信号水平。该模型结合了一系列合理的假设来控制其模式行为：在没有信号的情况下采用 SOP 命运和在足够高的信号下采用替代性表皮命运的细胞，在中间信号水平下表现出双稳态响应。来自细胞的抑制信号随细胞状态呈非线性变化，并超出直接邻居。结果 在原神经基因表达开始之前，Delta 表达的双峰梯度驱动了 Notch 活性；由于顺式抑制，Notch 仅在中间 Delta 水平区域被激活。这定义了第一组三个原神经条纹的抑制模板。Notch 活动的空间模式随着这些第一个原神经条纹的出现而动态变化，形成了第二组插入条纹的负模板。最终，每个条带通过 Notch 信号分解成一行孤立的 SOP。因此，Notch 通过自组织过程介导了原神经条纹图案和 SOP 选择。模型的模拟，用描述在体内观察到的原神经独立信号的时间依赖性抑制梯度，概括了原神经条纹的连续出现和分辨率。在模型和实验中，相互抑制推动了原神经组的逐渐细化，伴随着原神经活动的积累。条纹两侧的细胞首先被排除在外，这样条纹就会在分离的 SOP 出现之前变窄。就模型而言，细胞内在双稳态允许在条纹中心具有较高原神经活性的细胞逃避足以排除侧面细胞的抑制水平。非线性信号允许从扩展的原神经组内的弱相互抑制平滑过渡到来自新兴 SOP 的强侧抑制，确保原神经组的磨损继续进行，直到只剩下孤立的细胞。最后，该模型正确预测了影响 Notch 活动模式、Delta 的水平和活动以及信号范围的扰动实验的结果。结论我们的结果表明，自组织的 Notch 信号可以在组织范围内建立条纹和点图案。由 Delta 的初始梯度介导的瞬时空间偏差通过细胞间相互作用转导，以产生更精细的前神经条纹和刚毛行图案。来自外在位置线索和自组织的输入，有时被认为是命运模式的竞争范式，在刷毛发育过程中结合并通过相同的信号运作。自组织 Notch 动力学可以提供灵活的基础，以响应不同的输入生成不同的模式。自组织的刷毛图案。（顶部）来自预模式（绿色，Delta）和细胞间相互作用的输入 [红色，Achaete；蓝色，无意义；绿色，E(spl)m3-HLH] 结合在果蝇胸部建立规则的刷毛行模式。（底部）结合细胞内在双稳态（洋红色，SOP；绿色，表皮）的数学模型概括了原神经条纹图案和 SOP（红色和洋红色，细胞状态；绿色，信号）的单选。发育中的多细胞生物中空间模式的出现依赖于位置线索和细胞间通讯。果蝇的感觉器官形成了一种范式，其中这些器官以两个不同的步骤运作：Prepattern 因子驱动局部原神经活动，然后 Notch 介导的侧向抑制会挑出神经前体。在这里，我们展示了通过 Notch 信号的自组织也建立了前神经条纹，这些条纹分解成飞胸上的一排排感觉刷毛。由 Delta 配体表达梯度启动的图案形成通过条纹之间和条纹内的抑制性信号传导进行。因此，Notch 信号可以支持自组织的组织模式，因为预模式被细胞间相互作用转导为细胞命运的精细排列。由 Delta 配体表达梯度启动，通过条带之间和条带内的抑制性信号传导进行。因此，Notch 信号可以支持自组织的组织模式，因为预模式被细胞间相互作用转导为细胞命运的精细排列。由 Delta 配体表达梯度启动，通过条带之间和条带内的抑制性信号传导进行。因此，Notch 信号可以支持自组织的组织模式，因为预模式被细胞间相互作用转导为细胞命运的精细排列。