Signaling at a distance mediated by vesicles on novel cellular protrusions

摘要 阐明细胞间通讯的分子机制的重要性 怎么说都不过分细胞间通讯是进化的基础， 后生动物;然后随着生物体变大，信号的传递距离假设 至关重要。长距离信号，细胞必须通过 几个细胞直径对于发育和体内平衡都是至关重要的。不足 正确执行该过程常常导致疾病或死亡。对人类癌症的研究 提供了大量示例，说明当信令流程的某个组件 糟了在过去的几十年里，许多信号通路已经被表征， 大量参与细胞间信号转导的分子， 配体及其同源细胞受体。然而，差距仍然存在， 存在于已知的信号传播方式中。基于扩散的 60多年前提出的传播模型一直是主导范式。这 在发育生物学中， 预测信号分子通过组织被动扩散时形成的梯度。 然而，关于这些模型能在多大程度上解释 各种信号在多个小区直径的距离上传输。 最近，包括我们自己在内的几个研究小组已经表明，信号分子可以 也可以通过直接的细胞-细胞接触在这样的距离上准确地递送， 细长的细胞突起的延伸（也称为信号丝状伪足）。我们有 发现了一种新的从斑马鱼色素细胞延伸出来的突起， 名为“airinemes " Airinemes已被视为条纹图案不可或缺的组成部分 基于其介导的长距离Delta-Notch信号传导在斑马鱼表皮中形成 不同的色素细胞类型有趣是，我们还发现， 长距离细胞间信号传导依赖于皮肤驻留巨噬细胞的参与。 总的来说，我们的研究结果表明，信号传播的机制可以涉及更多 而不仅仅是分子的被动扩散。此外，我们随后发现， 从表皮的其它细胞类型，例如，角质形成细胞，这表明空气丝介导的 信号传导可以是至少在该组织中的通用机制，如果不是其它组织的话。虽然 我们所描述的空丝素/巨噬细胞介导的信号传导已经被清楚地验证为 发生在体内，这种信号如何完成的分子和细胞细节仍然是未知的。 没有充分描述。这些细节是在这种模式下连接异常的关键第一步 与脊椎动物各种病理的发生有关。在本提案中，我们将 解决了确定空中环境如何实现目标特异性所必需问题， 有一个特定的皮肤巨噬细胞亚群， 信号传导，并确定空气素在斑马鱼角质形成细胞中提供什么功能。的 这些问题的答案不仅会扩展我们对基本细胞策略的看法， 用于旁分泌信号，但也可以提供检测生物医学 也许能够在人类病理生理学中信号出错时干预这一过程。

Abstract The importance of elucidating the molecular mechanisms that underlie cell-to-cell communication is impossible to overstate. Intercellular communication formed the foundation for the evolution of metazoans; then as organisms grew larger, the transduction of signals over distance assumed crucial importance. Long-range signaling in which cells must communicate accurately over several cell diameters is vital both during development and for homeostasis. Deficiencies in the proper execution of the process often results in disease or death. The study of human cancers provides numerous examples of what can happen when a component of a signaling process goes bad. Numerous signaling pathways have been characterized over the past few decades, and a large number of the molecules involved in intercellular signal transduction, both extracellular ligands and their cognate cellular receptors, have been identified. However, gaps still exist at present in what is known of the means by which signals are propagated. The diffusion-based propagation model suggested more than 60 years ago has been the dominant paradigm. This has been particularly true in developmental biology regarding the impact of concentration gradients that are predicted to form as signaling molecules passively diffuse through tissues. Nevertheless, debate has continued on how well such models can explain the precision by which various signals are transmitted over distances of multiple cell diameters. Recently, several research groups including our own have shown that signaling molecules can also be delivered accurately over such distances by direct cell-cell contact that involves the extension of long, thin cellular protrusions (also referred to as signaling filopodia). We have identified a novel variety of such protrusions extending from zebrafish pigment cells that we have named ‘airinemes.’ Airinemes have been seen to be an indispensable component of stripe pattern formation in zebrafish epidermis based on their mediation of long-distance Delta-Notch signaling between pigment cell types. Intriguingly, we have also discovered that this airineme-mediated long-range intercellular signaling is dependent on participation of skin-resident macrophages. Collectively, our findings denote that mechanisms of signal propagation can involve much more than mere passive diffusion of molecules. Moreover, we subsequently found airinemes protruding from other cell types of the epidermis, e.g., keratinocytes, suggesting that airineme-mediated signaling may be a general mechanism in at least that tissue if not others. Although the airineme/macrophage-mediated signaling that we have described has been clearly validated as occurring in vivo, the molecular and cellular details of how this signaling is accomplished are still not sufficiently described. Those details are a crucial first step in linking anomalies in this mode of signaling with the occurrence of various pathologies in vertebrates. In this proposal we will address questions essential to establishing how airinemes achieve target specificity, whether there is a particular subset of skin-resident macrophages that promotes airineme-mediated signaling, and determining what functions airinemes provide in zebrafish keratinocytes. The answers to these questions will not only expand our view of fundamental cellular strategies employed in paracrine signaling but could also provide a basis for detecting where biomedicine might be able to intervene in the process when signaling goes awry in human pathophysiology.